N-sulfonylindoline derivatives, their preparation and the pharmaceutical compositions in which they are present

ABSTRACT

The invention relates to N-sulfonyl derivatives of formulae (I)&#39;&#39; and (I)&#39;    &lt;IMAGE&gt; (I)&#39;&#39;  &lt;IMAGE&gt; (I)&#39;  and to pharmaceutical compositions in which they are present. The compounds have an affinity for the vasopressin and ocytocin receptors.

This application is a continuation-in-part of application Ser. No.07/737,655, filed on Jul. 30, 1991, now abandoned.

The present invention relates to N-sulfonylindoline derivatives, totheir preparation and to the compositions in which they are present.

U.S. Pat. No. 3 838 167 describes some N-sulfonylindole derivatives ofthe formula ##STR2## in which R'₁ is hydrogen, an alkyl or a substitutedor unsubstituted phenyl;

R'₂ is a halogen, an alkyl, an alkoxy, a nitro or trifluoromethyl;

R'₃ is an alkyl, a phenyl or an alkylphenyl;

R'₄ is an alkyl, a substituted or unsubstituted phenyl, an alkoxy or aphenoxy; and

n'=0, 1 or 2.

These compounds of formula 1 are synthesis intermediates for thepreparation of indole derivatives active on the central nervous system,said derivatives having the formula ##STR3## in which R' is an alkyl, asubstituted or unsubstituted phenyl or a hydroxyl.

The N-sulfonylindoline derivatives according to the present inventionhave an affinity for the vasopressin and ocytocin receptors.

Vasopressin is a hormone known for its antidiuretic effect and itseffect in the regulation of the arterial pressure. It stimulates severaltypes of receptors--V₁, V₂, V_(1a), V_(1b) --and thus exertscardiovascular, central, hepatic, antidiuretic and aggregating effects.Vasopressin receptor antagonists can affect the regulation of thecentral and peripheral circulation, especially the coronary, renal andgastric circulation, as well as the metabolism of water and the releaseof adrenocorticotrophic hormone (ACTH). The vasopressin receptors, likethe ocytocin receptors, are also found on the smooth muscle of theuterus. Ocytocin has a peptide structure similar to that of vasopressin.Its receptors are also found on the myoepithelial cells of the mammarygland and in the central nervous system (Presse Medicale, 1987, 16(10),481-485, J. Lab. Clin. Med., 1989, 114(6), 617-632, and Pharmacol. Rev.,1991, 43(1), 73-108).

Thus the compounds according to the invention are useful especially inthe treatment of complaints of the central nervous system, thecardiovascular system and the gastric sphere in humans and animals.

According to a first aspect, the present invention relates to compoundsof the formula ##STR4## in which R₁ is a halogen atom, a C₁ -C₄ alkyl, ahydroxyl, a C₁ -C₄ alkoxy, a benzyloxy group, a cyano group, atrifluoromethyl group, a nitro group or an amino group;

R₂ is a C₁ -C₆ alkyl, a C₃ -C₇ cycloalkyl, a C₅ -C₇ cycloalkene or aphenyl which is unsubstituted or monosubstituted or polysubstituted by aC₁ -C₄ alkyl, a C₁ -C₄ alkoxy, a halogen, a trifluoromethyl group, anitro group or an amino group;

R₃ is a hydrogen atom or a C₁ -C₄ alkyl;

R₄ is a carboxyl group, an alkoxycarbonyl group in which the alkyl groupis C₁ -C₆, a benzyloxycarbonyl group or a carboxamide group of theformula CONR₆ R₇ ;

R₅ is a C₁ -C₄ alkyl, a 1-naphthyl, a 2-naphthyl, a5-dimethylamino-1-naphthyl or a phenyl which is unsubstituted orsubstituted by one or more substituents selected from a halogen atom, aC₁ -C₄ alkyl, a tri-fluoromethyl group, a nitro group, an amino groupwhich is free or substituted by one or 2 C₁ -C₄ alkyls, a hydroxyl, a C₁-C₄ alkoxy, a C₁ -C₄ alkenoxy, a C₁ -C₄ alkylthio, a trifluoromethoxygroup, a benzyloxy group, a cyano group, a carboxyl group, a C₁ -C₄alkoxycarbonyl group, a carbamoyl group or aC₁ -C₄ alkylamido group, or,when m=0, R₅ can be a group ##STR5## R₆ and R₇ are each independentlyhydrogen, a C₁ -C₆ alkyl or a phenylalkyl in which the alkyl is C₁ -C₄,or R₆ and R₇ together form a group --(CH₂)_(p) --;

n is 0, 1 or 2;

m is 0, 1 or 2; and

p is 4, 5 or 6;

and their salts, where appropriate.

The compounds (I) exhibit cis-trans isomerism around the 2,3 bond of theindoline. The different isomers form an integral part of the invention.

By convention, the compounds (I) in which R₂ and R₄ are on the same sideof the ring are called the cis isomers.

By convention, the compounds (I) in which R₂ and R4 are on oppositesides of the ring are called the trans isomers. ##STR6##

Moreover, the compounds according to the invention have 2 asymmetriccarbon atoms. The optical isomers of the compounds (I) form part of theinvention.

In the present description and in the claims which follow, halogen isunderstood as meaning a fluorine, chlorine, bromine or iodine atom;alkyl group is understood as meaning linear or branched hydrocarbongroups.

Preferred compounds (I) according to the invention are those in which atleast one of the following conditions is satisfied:

R₁ is a chlorine or bromine atom or a methoxy group and n=0;

R₂ is a chlorophenyl, a methoxyphenyl or a cyclohexyl;

R₃ is hydrogen;

R₄ is an alkoxycarbonyl in which the alkyl group is C₁ -C₆, or R₄ is acarboxamide group NR₆ R₇ in which R₆ and R₇ are C₁ -C₆ alkyls;

R₅ is a phenyl substituted in the 3 and 4 positions or in the 2 and 4positions by a methoxy group, or R₅ is a phenyl substituted in the 4position by a methyl group; and

m is 0.

The compounds (I) which are in the form of the cis isomers areparticularly preferred.

The following abbreviations are used in the description and theExamples:

DCM: dichloromethane

AcOEt: ethyl acetate

MeOH: methanol

EtOH: ethanol

Ether: ethyl ether

DMF: dimethylformamide

THF: tetrahydrofuran

TEA: triethylamine

DMSO: dimethyl sulfoxide

DIPEA: diisopropylethylamine

DCC: N,N'-dicyclohexylcarbodiimide

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

TBD: 1,5,7-triazabicyclo[4.4.0]dec-5-ene

DBN: 1,5-diazabicyclo[4.3.0]non-5-ene

DMAP: 4-dimethylaminopyridine

DMPU: 1,3-dimethyl-2-oxohexahydropyrimidinone

TMEDA: tetramethylethylenediamine

LDA: lithium diisopropylamide

HMPA: hexamethylphosphoramide

HOBT: 1-hydroxybenzotriazole hydrate

BOP: benzotriazolyloxytrisdimethylaminophosphonium hexafluorophosphate

TFA: trifluoroacetic acid

Lawesson's reagent:2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide

M.p.: melting point

Saline solution: water saturated with sodium chloride

Dry ice: solid carbon dioxide

TLC: thin layer chromatography

HPLC: high performance liquid chromatography

NMR: nuclear magnetic resonance

s: singlet

m: multiplet

bs: broad singlet

d: doublet

Hydrochloric water: dilute hydrochloric acid, about 1N

80% NaH: dispersion of sodium hydride in mineral oil (Janssen Chemica)

Me: methyl

Et: ethyl

iPr: isopropyl, Pr: propyl

iPentyl: isopentyl

iBu: isobutyl

tBu:tert-butyl, Bu: butyl

Bz: benzyl

Ph: phenyl

RT: room temperature

The present invention further relates to the method of preparing thecompounds (I).

This method comprises

a) reacting a sulfonyl derivative of the formula

    Hal--SO.sub.2 --(CH.sub.2).sub.m --R.sub.5                 (III)

in which Hal is a halogen, preferably chlorine or bromine, and R₅ is asdefined above for (I), with a 2-aminophenone derivative of the formula##STR7## in which R₁, R₂ and n are as defined above for (I);

b) treating the resulting compound of the formula ##STR8## with ahalogenated derivative of the formula ##STR9## in which Hal' is ahalogen, preferably bromine, and R₃ and R₄ are as defined above for (I);

c) cyclizing the resulting compound of the formula ##STR10## in a basicmedium in order to prepare the compound (I) according to the invention;and

d) separating the cis and trans isomers of the compound (I), ifappropriate.

The 2-aminophenone derivatives (II) are known or prepared by knownmethods such as those described by A.K. Singh et al., Synth. Commun.,1986, 16(4), 485, and G.N. Walker, J. Org. Chem., 1962, 27, 1929.

The halogenosulfonyl derivatives (III) are known or prepared by knownmethods. Thus, for example, 4-dimethylaminophenylsulfonyl chloride isprepared according to C.N. SUKENIK et al., J- Amer. Chem. Soc., 1977,99, 851-858; p-benzyloxysulfonyl chloride is prepared according toEuropean patent application 229 566.

An alkoxysulfonyl chloride is prepared from a sodium alkoxysulfonate,which is itself prepared by reacting an alkyl halide with sodiumhydroxyphenylsulfonate. The 2-amino-2-trifluoromethylbenzophenones andthe other trifluoromethylated derivatives are prepared according to U.S.Pat. No. 3 341 592.

2,4-Dimethoxybenzylsulfonyl chloride is prepared according to J. Am.Chem. Soc., 1952, 74, 2008.

The halogenated derivatives (V) are known or prepared by known methodssuch as those described by A.I. Vogel: A Text Book of Practical OrganicChemistry: Longman, 3rd ed. 1956, p. 383, or G. Kirchner et al., J. Am.Chem. Soc., 1985, 107, 24, 7072.

Step a) of the method is carried out in pyridine by heating at atemperature between room temperature and the boiling point of thesolvent for a period of time of between a few hours and a few days. Ifappropriate, the reaction can be carried out in the presence ofdimethylaminopyridine, which is used in a catalytic or stoichiometricamount.

Step b) of the method is carried out between the sulfonamide (IV) and anexcess of the halogenated derivative in a solvent such asdimethylformamide or dimethyl sulfoxide, under an inert atmosphere, at atemperature of between 0° C. and room temperature, for a time of betweena few hours and 24 hours, in the presence of sodium hydride.

Step c) of the method is closely related to an aldolization reaction:The group CH--R₃ in the α position of the ester or the amide isdeprotonated and the carbonyl group of the phenone then acts like aninternal electrophile, resulting in cyclization with the appearance oftwo asymmetric carbons (C*).

The reaction can be illustrated by the following scheme: ##STR11##

The principles of the aldol addition reaction have been reviewed by C.H.Heathcock in Asymmetric Synthesis, vol. 3: Stereodifferentiatingaddition reactions, part B, 111-212, Academic Press, 1984, edited byJ.D. Morrison.

It is known that the aldol addition of achiral ester anions (or amideanions) on to achiral bases gives rise to the formation of 2 racemicdiastereoiso-mers of β-hydroxyesters (or β-hydroxyamides) in a ratiowhich depends largely on the experimental conditions used. The followingmay be mentioned among these conditions: the nature of the inorganic ororganic base used, the nature of the cations or counterions, thepossible presence of additives in the reaction medium, the solvent, thereaction temperature and the structure of the compound undergoing thisreaction.

If R₄ is a carboxamide group CONR₆ R₇, in which R₆ and R₇ are as definedabove for (I), it is possible to use sodium hydroxide in water, in thepresence of a cosolvent, with or without the addition of a phasetransfer catalyst.

This reaction can be carried out using organic bases, for example:

tertiary organic bases such as triethylamine,

guanidines such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene, or

amidines such as 1,8-diazabicyclo[5.4.0]undec-5-ene or1,5-diazabicyclo[4.3.0]non-5-ene,

in a solvent or a mixture of solvents selected for example from benzene,THF, dichloromethane, methanol and dimethylformamide; the reaction iscarried out under an inert atmosphere at between 25° and 110° C.; theamount of base used is at least stoichiometric; the reaction can also becarried out without a solvent, at the temperature of the bath.

It is also possible to use an alcoholate of a primary, secondary ortertiary alcohol with lithium, sodium, potassium, calcium or magnesium.

The alcoholate is used in a catalytic or stoichiometric amount in ananhydrous solvent, for example an alcohol (if appropriate in thepresence of a cosolvent such as THF), or else in a stoichiometric amountin THF, DMF or DMSO, if appropriate in the presence of crown ethers, forexample dicyclohexyl-18 crown-6; the reaction is carried out at between0° and 80° C. It is also possible to use a base such as sodium hydride,lithium hydride or potassium hydride, in a solvent such as, for example,ethyl ether, THF, benzene or DMF, or else alkali metal amides in asolvent such as aqueous ammonia, ether or toluene, at a temperature ofbetween -30° C. and 110° C.

The use of an amide of the type RR'NLi or RR'NMgBr, in which R and R'are monovalent radicals, as a deprotonating agent is a method of formingenolates of esters or amides, which are intermediates in thealdolization reaction; this method has recently been reviewed by R.E.Ireland et al., J. Org. Chem., 1991, 56, 650. The reaction solvent canbe benzene, hexane or THF used in anhydrous form under an inertatmosphere. Adjuvants such as LiF, LiCl, LiBr, LiI, LiBu, TMEDA, DMPU,HMPA or a crown ether can be added (M. Murakate et al., J. Chem. Soc.Chem. Commun., 1990, 1657). The influence of the reaction conditions onthe proportion of each of the isomers formed has been studied. By way ofexample, there may be mentioned the use of lithium diisopropylamide at-78° C. in anhydrous THF under an inert atmosphere, or in THF in thepresence of additives such as, for example, tetramethylenediamine, DMPUor HMPA. Examples of other known amides which can be used are lithiumcyclohexylamide and lithium 2,2,6,6-tetramethylcyclohexylamide. It isalso possible to prepare other amides by reacting the requisite amountof butyllithium in hexane with linear or cyclic secondary amines, thereaction taking place in one of the solvents mentioned above. Finally,various publications describe amides of optically active secondaryamines: L. Duhamel et al., Bull. Soc. Chim. France, 1984, II, 421; J.K.Whitesell et al., J. Org. Chem., 1980, 45, 755; M. Murakata et al., J.Chem. Soc. Chem. Comm., 1990, 1657; M. Yamaguchi, Tetrahedron Lett.,1986, 27(8), 959; P.J. Cox and N.S. Simpkins, Tetrahedron: Asymmetry,1991, 2(1), 1.

The silylamides of lithium, sodium or potassium constitute another groupof bases which can be used, among which there may be mentioned (Me₃ Si)₂NLi, (Me₂ PhSi)₂ NLi, (Et₃ Li)₂ NLi, (Me₃ Si)₂ NK and (Me₃ Si)₂ NNa.

It is also possible to use mixed amides such as those described by Y.Yamamoto, Tetrahedron, 1990, 46, 4563, for example the lithium salt ofN-(trimethylsilyl)benzylamine or an analog in which the benzylamine isreplaced with a chiral primary amine such as (R)- or(S)-α-methylbenzylamine.

When chiral amides are used, the 2 diastereoisomers, cis and trans, cantogether or independently of one another exhibit an optical activitycreated by asymmetric induction and enantiomeric enrichment. Theproportion of each of the enantiomers is then determined on a chiralHPLC column.

In step d), the 2 isomers of the compound (I) formed are extracted bythe conventional methods and separated by chromatography or fractionalcrystallization.

If appropriate, the optical isomers of each of the cis and trans isomersare separated, for example by preparative chromatography on a chiralcolumn.

If the 2 isomers of the compounds (I) are difficult to separate by thecustomary methods, it is also possible to prepare a compound of theformula ##STR12## in which R₁, R₂, R₃, R₄, R₅, m and n are as definedabove for (I), by reacting hexamethyldisilazane with the correspondingcompound (I). The reaction is carried out in the presence of a catalyticamount of imidazole by heating to 60°-120° C. under an inert atmosphere.The silyl ester is obtained by crystallization from the medium or afterchromatography. The 2 isomers of (VII) are separated by chromatographyon silica and each isomer of (VII) is then hydrolyzed in an alkalinemedium to give each isomer of (I).

Several methods can be used to differentiate and characterize the cisisomer and the trans isomer of a compound (I). If R₃ is hydrogen, acomparative analysis is performed by high field NMR (at 250MHz) coupledfor example with a study of the Overhauser effect (NOE) between, forexample, the proton of the indoline (R₃ =H) and the proton of thehydroxyl.

If R₄ is a carboxamide group, the IR spectra of the cis isomer and thetrans isomer in solution in DCM are different. The cis isomer mostcommonly has a strong, fine and symmetrical absorption band at around3550-3520 cm⁻¹, due to the hydroxyl vibration, whereas the trans isomerhas no resolved vibration band in this region.

By means of the data collected, it has been found that the cis isomer isgenerally the more mobile in TLC on an aluminum oxide plate (60F254neutral, type E, Merck), the eluent being DCM containing variableproportions of AcOEt. Similarly, in chromatography on an alumina column(aluminum oxide 90, particle size 0.063-0.200 mm), the cis isomer ismost commonly eluted first, the eluent being DCM containing variableproportions of AcOEt or MeOH.

If R₄ is an ester group, it is possible to carry out the TLC on a silicaplate (Kieselgel 60F250, Merck) using DCM as the eluent; when the TLC iscarried out on a mixture of the isomers, the cis isomer is generally themore mobile.

Thus the cis or trans isomerism of a compound (I) according to theinvention can most often be determined by an analytical method. It isalso possible to utilize the analogy between similar compounds orbetween compounds prepared from one another.

The compounds (I) in which R₄ is a carboxyl group are prepared bydebenzylation of the compounds (I) in which R₄ is a benzyloxycarbonylgroup by means of catalytic hydrogenation, for example in the presenceof palladium-on-charcoal.

The compounds (I) in which R4 is a carboxamide group, CONH₂, can beprepared from the corresponding compounds (I) in which R₄ is a carboxylgroup, for example by a conventional coupling method used in peptidesynthesis, for example in the presence of BOP and DIPEA.

A compound (I) in which R₁ is an amino group and/or a compound in whichR₅ is a phenyl group which is substituted by an amino can be prepared bythe conversion of a compound (VI), obtained in step b), in which R₁ is anitro group and/or R₅ is a phenyl group substituted by a nitro, theother substituents having the meanings desired for (I), by means ofcatalytic hydrogenation, for example in the presence ofpalladium-on-charcoal or rhodium-on-alumina.

The compounds of formula (VI) obtained at the end of step b) are noveland form part of the invention.

According to a second aspect, the present invention relates to compoundsof the formula ##STR13## in which R'₁ is a halogen atom a C₁ -C₄ alkyl,a hydroxyl, a C₁ -C₄ alkoxy, a benzyloxy group, a cyano group, atrifluoromethyl group, a nitro group or an amino group;

R'₂ is a C₁ -C₆ alkyl, a C_(3-C) ₇ cycloalkyl, a C₅ -C₇ cycloalkene or aphenyl which is unsubstituted or monosubstituted or polysubstituted by aC₁ -C₄ alkyl, a C₁ -C₄ alkoxy, a halogen, a trifluoromethyl group or anamino group, or R'₂ is a nitrophenyl which is unsubstituted ormonosubstituted by a trifluoromethyl group or monosubstituted orpolysubstituted by a C₁ -C₄ alkyl or a halogen;

R'₃ is a hydrogen atom;

R'₄ is a carbamoyl group of formula CONR₆ R₇ ;

R'₅ is a C₁ -C₄ alkyl; a 1-naphthyl; a 2-naphthyl; a5-dimethylamino-1-naphthyl; a phenyl which is unsubstituted orsubstituted by one or more substituents selected from a halogen atom, aC₁ -C₄ alkyl, a trifluoromethyl group, an amino group which is free orsubstituted by one or 2 C₁ -C₄ alkyls, a hydroxyl, a C₁ -C₄ alkoxy, a C₂-C₄ alkenoxy, a C₁ -C₄ alkylthio, a trifluoromethoxy group, a benzyloxygroup, a cyano group, a carboxyl group, a C₁ -C₄ alkoxycarbonyl group, acarbamoyl group which is free or substituted by one or two C₁ -C₄ alkylsor a C₁ -C₄ alkylamino group, or R'₅ is a nitrophenyl which isunsubstituted or by a trifluoromethyl group or a C₂ -C₄ alkenoxy ormono- or polysubstituted by a halogen, a C₁ -C₄ alkyl, a C₁ -C₄ alkoxy,a C₁ -C₄ alkythio, a trifluoromethoxy group or a benzyloxy group;

R'₆ is a C₁ -C₆ alkyl or R'₆ is similar to R'₇ ;

R'₇ is a 4-piperidyl group or a 3-azetidinyl group, the said groupsbeing substituted or unsubstituted on the nitrogen by a C₁ -C₄ alkyl, bya benzyloxycarbonyl or by a C₁ -C₄ alkoxycarbonyl; a group (CH₂)_(r)which is itself substituted by a 2-, 3- or 4-pyridyl group, by ahydroxyl group or by an amino group which is free or substituted by oneor two C₁ -C₄ alkyls, a carboxyl group, C₁ -C₄ alkoxycarbonyl group, abenzyloxycarbonyl group or a carbamoyl group which is free orsubstituted by one or 2 C₁ -C₄ alkyls; or R'₆ and R'₇ together, with thenitrogen atom to which they are connected, form a heterocycle selectedfrom:

morpholine,

thiomorpholine,

thiazolidine or 2,2-dimethylthiazolidine, unsubstituted or substitutedby R₈,

piperazine, unsubstituted or substituted at the 4-position by a groupR"₈,

an unsaturated, 5-membered ring containing a single nitrogen atom andsubstituted by R₈ or a saturated, 3-, 4-, 5-, 6- or 7-membered ringcontaining a single nitrogen atom and substituted by R₈ and R₉ ;

R₈ is R'₈ or a group (CH₂)_(r) which is itself substituted by a hydroxylor by an amino which is free or substituted by one or two C₁ -C₄ alkyls;

R'₈ is a group (CH₂)_(q) which is itself substituted by a carboxylgroup, a C₁ -C₄ alkoxycarbonyl group, a benzyloxycarbonyl group, acarbamoyl group which is free or substituted by a hydroxyl or by one or2 C₁ -C₄ alkyls or an aminocarbothioyl group which is free orsubstituted by one or 2 C₁ -C₄ alkyls;

R"₈ is R'₈ or a group (CH₂)₂ NH₂ which is free or substituted by one ortwo C₁ -C₄ alkyls;

R₉ is hydrogen, a halogen, a group (CH₂)_(r) OR₁₀, a group (CH₂)_(r)NR₁₁ R₁₂, a group (CH₂)_(t) CONR₁₁ R'₁₁ or an azido group;

R₁₀ is hydrogen, a C₁ -C₄ alkyl, a mesyl or a tosyl;

R₁₁, R'₁₁ and R₁₂ are each a hydrogen or a C₁ -C₄ alkyl or R₁₁ ishydrogen and R₁₂ is a benzyloxycarbonyl or a C₁ -C₄ alkoxycarbonyl;

n is 0, 1 or 2;

m is 0, 1 or 2;

q is 0, 1, 2 or 3;

r is 0, 1, 2 or 3, with the limitation that r is not zero when R₈ or R₉is at the alpha-position of the intracyclic amide nitrogen;

t is 0 or 1;

as well as their possible salts.

The salts of the compounds of formula (I)' according to the presentinvention comprise those with inorganic or organic acids which makepossible a suitable separation or crystallization of the compounds offormula (I)', such as picric acid, oxalic acid or an optically activeacid, for example a mandelic acid or a camphosulfonic acid, and thosewhich forth pharmaceutically acceptable salts such as the hydrochloride,the hydrogensulfate, the dihydrogenphosphate, the methanesulfonate, themaleate, the fumarate or the 2-naphthalenesulfonate.

The salts of the compounds of formula (I)' also comprise the salts withorganic or inorganic bases, for example the salts of alkali oralkaline-earth metals such as the salts of sodium, potassium or calcium,the salts of sodium and potassium being preferred, or with an amine,such as trometamol, or even the salts of arginine or lysine or of anypharmaceutically acceptable amine.

The compounds (I)' exhibit cis-trans isomerism around the 2,3 bond ofthe indoline. The different isomers form an integral part of theinvention.

By convention, the compounds (I)' in which R'₂ and R'₄ are on the sameside of the ring are called the cis isomers.

By convention, the compounds (I)' in which R'₂ and R'₄ are on oppositesides of the ring are called the trans isomers. ##STR14##

Moreover, the compounds according to the invention have 2 asymmetriccarbon atoms or more when R'₄ contains one 1 or 2 asymmetric carbons.The optical isomers of the compounds (I) form part of the invention.

In the present description and in the claims which follow, halogen isunderstood as meaning a fluorine, chlorine, bromine or iodine atom;alkyl group is understood as meaning linear or branched hydrocarbongroups.

Preferred compounds (I)' according to the invention are those in whichat least one of the following conditions is satisfied:

R'₁ is a chlorine or bromine atom or a methoxy group and n=0;

R'₂ is a chlorophenyl, a methoxyphenyl or a cyclohexyl;

R'₄ is a group CONR'₆ R'₇ in which R'₆ and R'₇ or NR'₆ R'₇ have one ofthe following definitions;

NR'₆ R'₇ is a pyrrolidino group which is substituted at the 2-positionby a group (CH₂)_(q) which is itsel f substituted by a carboxyl orcarbamoyl group with q=0, 1, 2 or 3.

NR'₆ R'₇ is a piperidino group which is substituted at the 4-position byan amino group, a C₁ -C₄ alkylamino or a C₁ -C₄ dialkylamino,

NR'₆ R'₇ is a thiazolidino group which is substituted by a group(CH₂)_(q) which is itself substituted by a carboxyl or carbamoyl groupwith q=0, 1, 2 or 3.

NR₆ R₇ is a pyrrolidino group which is substituted at the 2-position bya group (CH₂)_(q) which is itself substituted by a carboxyl or carbamoylgroup with q=0, 1, 2 or 3 and which is substituted at the 4-position byan amino group, a C₁ -C₄ alkylamino or a C₁ -C₄ dialkylamino;

R'₆ is a C₁ -C₄ alkyl and R'₇ is a group (CH₂)₄ which is itselfsubstituted by a carboxyl group or a carbamoyl group with r=1, 2 or 3;

R'₅ is a phenyl substituted at the 3- and 4-position or at the 2- and4-position by a methoxy group, or R'₅ is a phenyl substituted at the4-position by a methyl group;

m=0.

The compounds (I)' which are in the form of the cis isomers areparticularly preferred. ##STR15## in which: R"₁ is a halogen atom, a C₁-C₄ alkyl, a hydroxyl, a C₁ -C₄ alkoxy, a benzyloxy group, a cyanogroup, a trifluoromethyl group, nitro group or an amino group;

R"₂ is a C₁ -C₆ alkyl, a C₃ -C₇ cycloalkene or a phenyl which isunsubstituted or monosubstituted or polysubstituted by a C₁ -C₄ alkyl, aC₁ -C₄ alkoxy, a halogen, a trifluoromethyl group or an amino group, orR"₂ is a nitrophenyl which is unsubstituted or monosubstituted by atrifluoromethyl group or monosubstituted or polysubstituted by a C₁ -C₄alkyl or a halogen;

R"₃ is a hydrogen atom;

R"₄ is a carbamoyl group of formula CONR"₆ R"₇ ;

R"₅ is a C₁ -C₄ alkyl; a 1-naphthyl; a 2-naphthyl; a5-dimethylamino-1-naphthyl; a phenyl which is unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of a halogen atom, a C₁ -C₄ alkyl, a trifluoromethyl gorup,an amino group which is free or substituted by one or two C₁ -C₄ alkyls,a hydroxyl, a C₁ -C₄ alkoxy, a C₂ -C₄ alkenoxy, a C₁ -C₄ alkylthio, atrifluoromethoxy group, a benzyloxy group, a cyano group, a carboxylgroup, a C₁ -C₄ alkoxycarbonyl group, a carbamoyl group which is free orsubstituted by one or two C₁ -C₄ alkyls or a C₁ -C₄ alkylamino group, orR"₅ is a nitrophenyl which is unsubstituted or monosubstituted by atrifluoromethyl group or a C₂ -C₄ alkenoxy or mono- or poly-substitutedby a halogen, a C₁ -C₄ alkyl, a C₁ - C₄ alkoxy, a C₁ -C₄ alkylthio, atrifluoromethoxy group or a benzyloxy group;

R"₆ and R"₇, together with the nitrogen atom to which they areconnected, form a saturated 5-membered ring containing a single nitrogenatom and substituted by a hydroxyl in a position which is other than thealpha-position of the nitrogen of the ring, a group (CH₂)_(r) OH, or agroup (CH₂)_(q) itself substituted by a hydroxyl, an amino group whichis free or substituted by one or two C₁ -C₄ alkyls, a carboxyl group, aC₁ -C₄ alkoxycarbonyl, a benzyloxycarbonyl group, a carbamoyl groupwhich is free or substituted by one or two C₁ -C₄ alkyls;

n is 0, 1 or 2;

m is 0, 1 or 2;

q is 0, 1, 2 or 3;

r is 1, 2 or 3;

as well as its possible salts.

The present invention further relates to the process for preparing thecompounds (I)'.

This process comprises

a) reacting a 2-aminophenone derivative of formula: ##STR16## in whichR'₁, R'₂ and n have the meanings indicated above for I, with a sulfonylderivative of formula:

    Hal--SO.sub.2 --(CH.sub.2).sub.m --R'.sub.5                (III)'

in which

Hal is a halogen, preferably chlorine or bromine,

m and R'₅ have the meanings indicated above for (I)';

b) treating the resulting compound of formula: ##STR17## with ahalogenated derivative of formula:

    Hal'--CH.sub.2 COA                                         (V)'

in which

Hal' is a halogen, preferably bromine, and A represents either the groupNR₆ R₇ or the group OR in which R is a tert-butyl or a benzyl;

c) deprotecting the resulting ester of formula: ##STR18##

under suitable conditions, if applicable, when A is OR;

d) treating, if applicable, the resulting acid from Step c) of formula:##STR19## or its acid chloride of formula: ##STR20##

with a compound HNR'₆ R'₇ according to suitable amide couplingtechniques;

e) cyclizing the resulting compound from Step b) or from Step d) offormula: ##STR21##

in a basic medium in order to prepare the compound (I) according to theinvention;

f) separating, if appropriate, the cis and trans isomers of the compound(I)' and, if appropriate, separating the enantiomers.

The 2-aminophenone derivatives (II)' are known or prepared by knownmethods, such as those described by A.K. Singh et al., Synth. Commun.1986, 16 (4), 485 and G.N. Walker, J. Org. Chem., 1962, 27, 1929. The2-amino-2'-trifluoromethylbenzophenones and the othertrifluoromethylated derivatives are prepared according to U.S. Pat. No.3,341,592.

2,4-dimethoxybenzenesulfonyl chloride is prepared according to J. Am.Chem. Soc., 1952, 74, 2008.

The sulfonyl derivatives of formula (III)' are known or prepared byknown methods. Thus, for example, 4-dimethylaminobenzenesulfonylchloride is prepared according to C.N. Sukenik et al., J. Am. Chem.Soc., 1977, 99, 851-858; p-benzyloxybenzenesulfonyl chloride is preparedaccording to European patent application EP 229,566.

The alkoxybenzenesulfonyl chloride is prepared from the sodiumalkoxybenzenesulfonate, which is itself prepared by reacting an alkylhalide with sodium hydroxybenzenesulfonate.

The halogenated derivatives of formula (V)' are known or prepared byknown methods, such as those described by A.I. Vogel: A Text Book ofPractical Organic Chemistry: Longman, 3rd ed. 1956, p. 383, or G.Kirchner et al., J. Am. Chem. Soc., 1985, 107, 24, 7072.

Step a) of the process is carried out in pyridine by heating at atemperature between room temperature and the boiling point of thesolvent for a period of time of between a few hours and a few days. Ifappropriate, the reaction can be carried out in the presence ofdimethylaminopyridine, which is used in a catalytic or stoichiometricamount.

Step b) of the process is carried out between the sulfonamide of formula(IV)' and an excess of the halogenated derivative of formula (V)', in asolvent such as dimethylformamide or dimethyl sulfoxide, under an inertatmosphere, at a temperature of between 0° C. and room temperature, fora time of between a few hours and 24 hours, in the presence of sodiumhydride.

When the group --NR'₆ R'₇ contains a second amine group, that is to saywhen R'₆ and/or R'₇ are substituted by an amino group, it is possible tochoose to use a halogenated derivative (V)' of formula Hal'--CH₂ --CO₂ Rin which R is a tert-butyl or a benzyl, in order to prepare theintermediates of formula (VIa) and then (VIb). In this case, Step c) forthe formation of the acid of formula (VIb) is carried out either by theaction of hydrogen in the presence of a catalyst such as palladium oncharcoal when R is benzyl, or in acid medium, when R is tert-butyl, forexample in the presence of TFA or in the presence of hydrobromic acid inacetic acid or even in the presence of ZnBr₂ in DCM.

Step d) is then carried out under the conventional conditions for amidecoupling, for example in the presence of BOP or HOBT and DCC.

The compounds HNR'₆ R'₇ are known or prepared by known methods. By wayof example, the stereospecific synthesis of (R)- and(S)-2-pyrrolidinylacetic acids is carried out according to H. Rueger etal. in Heterocycles, 1982, 19 (9), 1677 from a proline derivative ofsuitable configuration. The preparation of methylN-Boc-3,4-dehydro-α-prolinate is carried out according to J.R. Dormoy,Synthesis, 1982, 753. The preparation of optically pure derivatives ofpipecolic acid is described, for example, in Tetrahedron, 1992, 48 (3)431-442 and Tetrahedron, 991, 47 (24) 4039-4062.

The preparation of the derivatives of aziridinecarboxylic acid iscarried out according to K. Nakajima et al. in Bull. Chem. Soc. Jap.,1978, 51 (5), 1577.

Step e) of the process is closely related to an aldolization reaction:the methylene group in the α-position of the amide is deprotonated andthe carbonyl group of the phenone then acts like an internalelectrophile, resulting in cyclization with the appearance of twoasymmetric carbons (C^(*)).

The reaction can be illustrated by the following scheme: ##STR22##

The principles of the aldol addition reaction have been reviewed by C.H.Heathcock in Asymmetric Synthesis, vol. 3: Stereodifferentiatingaddition reactions, part B, 111-112; Academic Press, 1984, edited byJ.D. Morrison.

It is known that the aldol reaction of achiral amide anions gives riseto the formation of 2 racemic diastereoisomers of β-hydroxyamides in aratio which depends largely on the experimental conditions used. Thefollowing may be mentioned among these conditions: the nature of theinorganic or organic base used, the nature of the cations orcounterions, the possible presence of additives in the reaction medium,the solvent, the reaction temperature and the structure of the compoundundergoing this reaction.

When the groups R'₆ and R'₇ do not contain a group which is hydrolysablein alkaline medium, it is possible to use sodium hydroxide in water, inthe presence of a cosolvent, with or without the addition of a phasetransfer catalyst; it is also possible to use a quaternary ammoniumhydroxide, for example benzyltrimethylammonium hydroxide in methanol.

In order to carry out this aldolization reaction, it is also possible touse organic bases, for example:

guanidines such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene,

amidines such as 1,8-diazabicyclo[5.4.0]undec-5-ene or1,5-diazabicyclo[4.3.0]non-5-ene,

in a solvent or a mixture of solvents selected for example from benzene,THF, dichloromethane, methanol and dimethylformamide; the reaction iscarried out under an inert atmosphere at between -10° C. and 110° C. theamount of base used is at least stoichiometric; the reaction can also becarried out without a solvent, at the temperature of the bath.

Preferentially, Step e) of the process according to the invention iscarried out in the presence of 1,8diazabicyclo[5.4.0]undec-5-ene (DBU)in a solvent such as dichloromethane or methanol, at a temperature ofbetween -10° C. and the reflux temperature of the solvent.

It is also possible to use an alcoholate of a primary, secondary ortertiary alcohol with lithium, sodium, potassium, calcium or magnesium.

The alcoholate is used in a catalytic or stoichiometric amount in ananhydrous solvent, for example an alcohol (if appropriate in thepresence of a cosolvent such as THF), or else in a stoichiometric amountin THF, DMF or DMSO, if appropriate in the presence of crown ethers, forexample dicyclohexyl-18-crown-6; the reaction is carried out at between-15° C. and 80° C.

The use of an amide of the type RR'NLi or RR'NMgBr, in which R and R'are monovalent radicals, as a deprotonating agent is a method of formingenolates of amides, which are intermediates in the aldolizationreaction; this method has recently been reviewed by R.E. Ireland et al.,J. Org. Chem., 1991, 56, 650. The reaction solvent can be benzene,hexane or THF used in anhydrous form under an inert atmosphere.Adjuvants such as LiF, LiCl, LiBr, LiI, LiBu, TMEDA, DMPU, HMPA or acrown ether can be added. (M. Murakate et al., J. Chem. Soc. Commun.,1990, 1657). By way of example, there may be mentioned the use oflithium diisopropylamide at between -78° C. and -30° C. in anhydrous THFunder an inert atmosphere or in THF in the presence of additives suchas, for example, tetramethylenediamine, DMPU or HMPA. Examples of otherknown amides which can be used are lithium cyclohexylamide and lithium2,2,6,6-tetramethylcyclohexylamide. It is also possible to prepare otheramides by reacting the requisite amount of butyllithium in hexane withlinear or cyclic secondary amines, the reaction taking place in one ofthe solvents mentioned above.

Finally, various publications describe amides of optically activesecondary amines: L. Duhamel et al., Bull. Soc. Chim. France, 1984, II,421; J.K. Whitesell et al., J. Org. Chem., 1980, 45, 755; M. Murakata etal., J. Chem. Soc. Chem. Commun., 1990, 1657; M. Yamaguchi, TetrahedronLett., 1986, 27 (8), 959; P.J. Cox and N.S. Simpkins, Tetrahedron:Asymmetry, 1991, 2 (1), 1.

The silylamides of lithium, sodium or potassium constitute another groupof bases which can be used, among which there may be mentioned: (Me₃Si)₂ NLi, (Me₂ PhSi)₂ NLi, (Et₃ Si)₂ NLi, (Me₃ Si)₂ NK, (Me₃ Si)₂ NNa.

It is also possible to use mixed amides as described by Y. Yamamoto,Tetrahedron, 1990, 46, 4563, for example the lithium salt ofN-(trimethylsilyl)benzylamine or an analog in which the benzylamine isreplaced with a chiral primary amine such as (R)- or(S)-α-methylbenzylamine.

When the compound of formula (I)' to be prepared has 2 asymmetric carbonatoms, the use of chiral amides or alcoholates in Step e) makes possiblean enantiomeric enrichment of each of the cis or trans stereoisomers.The proportion of each of the enantiomers is then determined bymeasurement on a chiral high performance liquid chromatography column.

When the compound of formula (I)' to be prepared has 3 or 4 asymmetriccarbon atoms, the cyclization Step c) can be accompanied by adiastereoisomeric enrichment and the use of a suitable chiral base makesit possible to modify this diastereoisomeric enrichment.

In Step f), the cis and trans geometric isomers of the compound (I)'formed are extracted by conventional methods and separated bychromatography or fractional crystallization.

If appropriate, the optical isomers of each of the cis and trans isomersare separated, for example by preparative chromatography on a chiralcolumn followed, if appropriate, by a fractional crystallization or byformation of an optically active salt in the presence of a suitablyselected chiral acid or base.

Thus, when the compound according to the invention has 2 asymmetriccarbon atoms, the enantiomers can be separated by chiral HPLC.

When the compound according to the invention has 3 or 4 asymmetriccarbon atoms, the diastereoisomers can be separated by usingchromatographic methods and fractional crystallization methods.

Several methods can be used to differentiate and characterize the cisisomer and the trans isomer of a compound (I)'. When R'₃ is hydrogen, acomparative analysis is performed by high field NMR (250MHz), coupledfor example with the study of the Overhauser effect (N.O.E.) between,for example, the proton of the indoline (R₃ =H) and the proton of thehydroxyl.

The IR spectra of the cis isomer and the trans isomer in solution in DCMare different. The cis isomer most commonly has a strong, fine andsymmetrical absorption band at around 3550-3520 cm⁻¹, due to thehydroxyl vibration, whereas the trans isomer has no resolved vibrationband in this region.

By means of the data collected, it has been found that the cis isomer isgenerally the more mobile in TLC on an aluminum oxide plate (60F254neutral, Type E, Merck), eluting with DCM containing variableproportions of AcOEt. Similarly, in chromatography on an alumina column(aluminum oxide 90, particle size 0.063-0.200mm), the cis isomer is mostcommonly eluted first, the eluent being DCM containing variableproportions of AcOEt or MeOH.

Thus the cis or trans isomerism of a compound (I)' according to theinvention can most often be determined by an analytical method. It isalso possible to utilize the analogy between similar compounds orbetween compounds prepared from one another.

The absolute configuration of some compounds according to the inventionwas determined by an X-ray analysis. By deduction therefrom, taking intoaccount the value of the optical rotation, it is also possible to knowthe absolute configuration of other compounds obtained in an analogousfashion.

A compound (I)' in which R'₁ is an amino group and/or a compound inwhich R'₅ is a phenyl group which is substituted by an amino can beprepared by the conversion of a compound (VI)', obtained in Step b), inwhich R'₁ is a nitro group and/or R₅ is a phenyl group which issubstituted by a nitro, the other substituents having the meaningsdesired for (I)', by catalytic hydrogenation, for example in thepresence of palladium on charcoal, or rhodium on alumina or Raneynickel.

The compounds (I)' in which the substituents R'₆ and/or R₇ or the groupNR'₆ R'₇ contain a C₁ -C₄ alkoxycarbonyl group make it possible toobtain, by hydrolysis of the ester, the compounds (I)' in which R'₆and/or R'₇ or the group NR'₆ R'₇ contain a carboxyl group, the othersubstituents of (I)' being unchanged. Furthermore, the compounds inwhich R'₆ and/or R'₇ or NR'₆ R'₇ contain a carboxyl group make itpossible to obtain, by a conventional amide coupling reaction, thecompounds (I)' in which R'₆ and/or R'₇ or the group NR'₆ R'₇ contain acarbamoyl group which is free or substituted by one or two C₁ -C₄alkyls, the other substituents being identical.

Finally, the compounds (I)' in which R'₆ and/or R'₇ or the group NR'₆R'₇ contain a carbamoyl group make it possible to obtain, by a Hofmannrearrangement, the compounds (I)' in which R'₆ and/or R₇ or the groupNR'₆ R'₇ contain an amino group, the other substituents being identical(J. Org. Chem., 1979, 44 (10), 1746).

Thus, according to the present invention, the process for preparingcompounds (I)' in which R'₆ and/or R'₇ or the group NR'₆ R'₇ contain anamino group which is free or substituted by one or two C₁ -C₄ alkyls canhave two variants:

i) Step b) of the process is carried out by treating the compound (IV)'obtained in Step a) with a halogenated derivative (V)' of formulaHal'--CH₂ CONR'₆ R'₇ in which R'₆ and/or R'₇ or the group NR'₆ R'₇contain a precursor group of the amine, for example a carboxyester, acarboxyl or a carbamoyl; the cyclization Step e) is then carried out andthe precursor group of the amine is then converted into the amine, forexample the carboxyester group of the compound (I)' thus obtained ishydrolyzed into a carboxyl group, which is then converted into acarbamoyl group and then into an amino group by the Hofmannrearrangement.

ii) Step b) is carried out by treating the compound (IV)' obtained inStep a) with an halogenated derivative (V)' of formula Hal'--CH₂ COOR inwhich R is a benzyl or a tert-butyl; the ester of the compound (VIa)thus obtained is deprotected by a suitable treatment, according to Stepc); a coupling is then carried out with the compound HNR'₆ R'₇ in whichthe amino group of R'₆ and/or R'₇ is, if appropriate, protected; thecompound (VI)' thus obtained is then cyclized according to Step e); and,if appropriate, the compound (I)' in which the amino group is free isprepared by deprotection of the amine.

The compounds (I)' in which the groups R'₆ and/or R'₇ or the group NR₆R₇ contain a benzyloxycarbonyl or alkoxycarbonyl group as substituent ofan amine group make it possible to obtain the compounds (I)' in whichthe amine group is free, the other substituents being identical.

The compounds of formula (VI)', useful intermediates for the preparationof compounds (I)' according to the invention, are novel and form part ofthe invention. Likewise, the compounds (VIa) and (VIb) are novel andform part of the invention.

The present invention thus also relates to the compounds of formula:##STR23## in which A' is a group selected from: NR₆ R₇, OH, OtBu, OBz;

R'₁ is a halogen atom, a C₁ -C₄ alkyl, a hydroxyl, a C₁ -C₄ alkoxy, abenzyloxy group, a cyano group, a trifluoromethyl group, a nitro groupor an amino group;

R'₂ is a C₁ -C₆ alkyl, a C₃ -C₇ cycloalkyl, a C₅ -C₇ cycloalkene or aphenyl which is unsubstituted or monosubstituted or polysubstituted byC₁ -C₄ alkyl, a C₁ -C₄ alkoxy, a halogen, a trifluoromethyl group or anamino group, or R'₂ is a nitrophenyl which is unsubstituted ormonosubstituted by a trifluoromethyl group or monosubstituted orpolysubstituted by a C₁ -C₄ alkyl, a C₁ -C₄ alkoxy or a halogen;

R'₅ is a C₁ -C₄ alkyl; a 1-naphthyl; a 2-naphthyl; a5-dimethylamino-1-naphthyl; a phenyl which is unsub stituted orsubstituted by one or more substituents selected from a halogen atom, aC₁ -C₄ alkyl, a trifluoromethyl group, an amino group which is free orsubstituted by one or 2 C₁ -C₄ alkyls, a hydroxyl, a C₁ -C₄ alkoxy, a C₂-C₄ alkenoxy, a C₁ -C₄ alkylthio, a trifluoromethoxy group, a benzyloxygroup, a cyano group, a carboxyl group, a C₁ -C₄ alkoxycarbonyl group, acarbamoyl group which is free or substituted by one or two C₁ -C₄ alkylsor a C₁ -C₄ alkylamido group, or R'₅ is a nitrophenyl which isunsubstituted or monosubstituted by a trifluoromethyl group or a C₂ -C₄alkenoxy or mono- or polysubstituted by a halogen, a C₁ -C₄ alkyl, aC₁ - C₄ alkoxy, a C₁ -C₄ alkylthio, a trifluoromethoxy group or abenzyloxy group;

R'₆ is a C₁ -C₆ alkyl or R'₆ is similar to R'₇ ;

R'₇ is a 4-piperidyl group or a 3-azetidinyl group the said groups beingsubstituted or unsubstituted on the nitrogen by a C₁ -C₄ alkyl, by abenzyloxycarbonyl or by a C₁ -C₄ alkoxycarbonyl; a group (CH₂)_(r) whichis itself substituted by a 2-, 3- or 4-pyridyl group, by a hydroxylgroup or by an amino group which is free or substituted by one or two C₁-C₄ alkyls, a carboxyl group, a C₁ -C₄ alkoxycarbonyl group, abenzyloxycarbonyl group or a carbamoyl group which is free orsubstituted by one or 2 C₁ -C₄ alkyls; or R'₆ and R'₇ together, with thenitrogen atom to which they are connected, form a heterocycle selectedfrom:

morpholine,

thiomorpholine,

thiazolidine or 2,2-dimethylthiazolidine, unsubstituted or substitutedby R₈,

piperazine, unsubstituted or substituted at the 4-position by a groupR"₈,

an unsaturated, 5-membered ring containing a single nitrogen atom andsubstituted by R₈ or

a saturated, 3-, 4 -, 5-, 6 - or 7 -membered ring containing a singlenitrogen atom and substituted by R₈ and R₉ ;

R₈ is R'₈ or a group (CH₂)_(r) which is itself substituted by a hydroxylor by an amino which is free or substituted by one or two C₁ -C₄ alkyls;

R'₈ is a group (CH₂)_(q) which is itself substituted by a carboxylgroup, a C₁ -C₄ alkoxycarbonyl group, a benzyloxycarbonyl group, acarbamoyl group which is free or substituted by a hydroxyl or by one or2 C₁ -C₄ alkyls or an aminocarbothioyl group which is free orsubstituted by one or 2 C₁ -C₄ alkyls;

R"₈ is R'₈ or a group (CH₂)₂ NH₂ which is free or substituted by one ortwo C₁ -C₄ alkyls;

R₉ is hydrogen, a halogen, a group (CH₂)_(r) OR₁₀, a group (CH₂)_(r)NR₁₁ R₁₂, a group (CH₂)_(t) CONR₁₁ R'₁₁ or an azido group;

R₁₀ is hydrogen, a C₁ -C₄ alkyl, a mesyl or a tosyl;

R₁₁, R'₁₁ and R₁₂ are each a hydrogen or a C₁ -C₄ alkyl or R₁₁ ishydrogen and R₁₂ is a benzyloxycarbonyl or a C₁ -C₄ alkoxycarbonyl;

n is 0, 1 or 2;

m is 0, 1 or 2;

q is 0, 1, 2 or 3;

r is 0, 1, 2 or 3, with the 1 limitation that r is not zero when R₈ orR₉ is at the alpha-position of the intracyclic amide nitrogen;

t is 0 or 1;

According to another aspect of the present invention, the compounds (I)'according to the invention in which either R'₇ or the group NR₆ R'₇contains a carboxyl group are useful for the preparation of analogousdecarboxylated compounds.

According to this aspect, the invention relates to the use of thecompounds of formula (Ia) ##STR24## in which R'₁, R'₂, R'₃, R'₅, m and nhave the meanings indicated above for (I),

R_(VI) is a C₁ -C₆ alkyl,

RVII is a group (CH₂)_(r) COOH with r=1, 2 or 3,

or R_(VI) and R_(VII) together, with the nitrogen atom to which they areconnected, constitute a heterocycle selected from:

thiazolidine or 2,2-dimethylthiazolidine, substituted by a (CH₂)_(q)COOH group,

piperazine substituted at the 4-position by a (CH₂)_(q) COOH group,

an unsaturated, 5-membered ring containing a single nitrogen atom andsubstituted by a (CH₂)_(q) COOH group or a saturated, 3-, 4-, 5-, 6- or7-membered ring containing a single nitrogen atom and substituted by a(CH₂)_(q) COOH group.

with q=0, 1, 2 or 3

for the preparation of a compound of formula (I)" having the sameconfiguration around the 2,3 bond of the indoline as the startingmaterial ##STR25## in which R'₁, R'₂, R'₃, R'₅, m and n are as definedabove,

R'_(VI) is a C₁ -C₆ alkyl,

R'_(VII) is a group (CH₂)_(r) H,

or R'_(VI) and R'_(VII) together, with the nitrogen atom to which theyare connected, constitute a heterocycle selected from:

thiazolidine or 2,2-dimethylthiazolidine, substituted by a (CH₂)_(q) Hgroup,

piperazine substituted at the 4-position by a (CH₂)_(q) H group,

an unsaturated, 5-membered ring containing a single nitrogen atom andsubstituted by a (CH₂)_(q) H group or a saturated, 3-, 4-, 5-, 6- or7-membered ring containing a single nitrogen atom and substituted by a(CH₂)_(q) H group.

The free-radical decarboxylation reaction is carried out according to D.H. R. Barton et al. in J. Chem. Soc; Chem. Commun.; 1984, 1298.

The affinity of the compounds according to the invention for thevasopressin receptors was determined in vitro using the method describedin J. Biol. Chem., 1985, 260 (5), 2844-2851. This method consists instudying the displacement of tritiated vasopressin bound to the V₁ sitesof rat liver membranes. The 50% inhibitory concentrations (IC₅₀) of thecompounds according to the invention for the binding of tritiatedvasopressin are low, ranging up to 10⁻⁹ M.

Furthermore, the inhibition of the platelet aggregation induced byvasopressin was measured on a human platelet rich plasma (human PRP)using the method described in Thrombosis Res., 1987, 45, 7-16. Thecompounds according to the invention inhibit the aggregation induced by50 to 100 nM concentrations of vasopressin with low ID₅₀ values(inhibitory doses) which range up to 10⁻⁹ M. These results show theantagonistic activity of the compounds according to the inventiontowards the V₁ receptors.

The affinity of the compounds (I) or (I)' according to the invention forthe V₂ receptors was measured by a method adapted from P. Crause et al.,Molecular and Cellular Endocrinology, 1982, 28, 529-541.

The compounds according to the invention of cis configuration around the2,3 bond of the indoline have a marked selectivity for the V₁ receptors.

The affinity of the compounds (I) or (I)' according to the invention forthe ocytocin receptors was determined in vitro by the displacement oftritiated ocytocin bround to the receptors of a membrane preparation ofgestating rat glands. The IC₅₀ values of the compounds according to theinvention are low, of between 10⁻⁵ M and 10⁻⁸ M.

The compounds according to the invention are active after administrationby various routes, especially orally.

No sign of toxicity is observed with these compounds at thepharmacologically active doses.

Thus the compounds according to the invention can be used in thetreatment or prevention of various vasopressin-dependent complaints,especially cardiovascular complaints such as hypertension, cardiacinsufficiency, thrombosis or coronary vasospasm, in particular insmokers; complaints of the central nervous system, for example cerebraledemas, psychotic states, appetite disorders or memory disorders;complaints of the renal system, such as renal vasospasm or necrosis ofthe renal cortex; and complaints of the gastric system, for exampleulcers or else the syndrome of inappropriate secretion of antidiuretichormone (SIADH).

The compounds according to the invention can also be used asantiemetics, especially in motion sickness, and as antiproliferativeagents, for example in cancer or atherosclerosis.

In woman, the compounds according to the invention can also be used forthe treatment of dysmenorrhea or premature labor.

The present invention further relates to pharmaceutical compositionscontaining an effective dose of a compound according to the invention,or of a pharmaceutically acceptable salt, and suitable excipients. Saidexcipients are chosen according to the pharmaceutical form and thedesired mode of administration.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical,intratracheal, intranasal, transdermal or rectal administration, theactive principles of formula I above, or their possible salts, can beadministered to animals and humans in unit forms of administration,mixed with conventional pharmaceutical carriers, for the prophylaxis ortreatment of the above disorders or diseases. Appropriate unit forms ofadministration include forms for oral administration, such as tablets,gelatin capsules, powders, granules and solutions or suspensions to betaken orally, forms for sublingual, buccal, intratracheal or intranasaladministration, forms for subcutaneous, intramuscular or intravenousadministration and forms for rectal administration. For topicalapplication, the compounds according to the invention can be used increams, ointments or lotions.

To obtain the desired prophylactic or therapeutic effect, the dose ofactive principle can vary between 0.01 and 50 mg per kg of body weightand per day.

Each unit dose can contain from 0.5 to 1000 mg, preferably from 1 to 500mg, of active ingredients in combination with a pharmaceutical carrier.This unit dose can be administered 1 to 5 times per day so as toadminister a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg.

If a solid composition in the form of tablets is prepared, the mainactive ingredient is mixed with a pharmaceutical vehicle such asgelatin, starch, lactose, magnesium stearate, talc, gum arabic or thelike. The tablets can be coated with sucrose, a cellulose derivative orother appropriate substances or they can also be treated so as to have aprolonged or delayed activity and so as to release a predeterminedamount of active principle continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with a diluent and pouring the resulting mixture intosoft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration inthe form of drops can contain the active ingredient in combination witha sweetener, which is preferably calorie-free, and methylparaben andpropylparaben as antiseptics, as well as with a flavoring and anappropriate color.

Water-dispersible granules or powders can contain the active ingredientmixed with dispersants or wetting agents or with suspending agents suchas polyvinylpyrrolidone, as well as with sweeteners or taste correctors.

Rectal administration is effected using suppositories which are preparedwith binders melting at the rectal temperature, for example cocoa butteror polyethylene glycols.

Parenteral administration is effected using aqueous suspensions,isotonic saline solutions or sterile and injectable solutions whichcontain pharmacologically compatible dispersants and/or wetting agents,for example propylene glycol or butylene glycol.

The active principle can also be formulated as microcapsules, ifappropriate with one or more carriers or additives.

Apart from the products of formula I above or one of thepharmaceutically acceptable salts, the compositions of the presentinvention can contain other active principles which may be useful in thetreatment of the disorders or diseases indicated above.

Thus the present invention relates to pharmaceutical compositionscontaining a plurality of active principles in association, one of whichis a compound according to the invention.

The following examples illustrate the invention.

The compounds are characterized by their melting point (M.p. °C.) (ortheir boiling point B.p.) and/or their NMR spectrum recorded at 200MHzin DMSO, and/or their optical rotation (αD) measured at 25° C. (exceptwhen otherwise indicated).

The measured value of the optical rotation is dependent on the amount ofresidual solvent present in the prepared product.

Except when otherwise indicated, the designation "cis isomer" or "transisomer" signifies that the isolated compound is a mixture ofenantiomers, either of cis configuration or of trans configuration.

The optical purity of the compounds is studied by high performanceliquid chromatography (HPLC).

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1, 2, 3, 4, 5 and 6 show NMR spectra of the compounds of theinvention.

The examples 1 to 146 illustrate the preparation of compounds of formula(I).

The examples 1a to 119a illustrate the preparation of compounds offormula (I)'.

EXAMPLES 1 AND 2

Methyl5-chloro-3-cyclohexyl-3-hydroxy-1-(naphthyl-1-sulfonyl)indoline-2-carboxylate,cis isomer, trans isomer

A) 5-Chloro-2-[(naphthyl-1-sulfonyl)amino]cyclohexylphenone

A mixture containing 3 g of 2-amino-5-chloro-cyclohexylphenone and 3.2 gof naphthyl-1-sulfonyl chloride is heated in pyridine at 100° C. for 8hours. The pyridine is evaporated off, water is added, the mixture isextracted with ethyl acetate and the extract is then filtered on silicausing dichloromethane as the eluent to give 4.27 g of the expectedproduct.

After recrystallization from a DCM/isopropyl ether mixture,m.p.=140-142° C.

B)5-Chloro-2-[N-(methoxycarbonylmethyl)-N-(naphthyl-1-sulfonyl)amino]cyclohexylphenone

4.27 g of the product obtained in the previous step are dissolved in 20ml of anhydrous DMF under argon. 320 mg of 80% sodium hydride are addedat 0° C., after 20 minutes 6.1 g of ethyl bromoacetate are then addedover 30 minutes and the mixture is stirred for 3 hours at roomtemperature. After extraction, the crude product obtained isrecrystallized from a DCM/isopropyl ether mixture to give 2.45 g of theexpected compound.

M.p.=130-132° C.

C) Methyl5-chloro-3-cyclohexyl-3-hydroxy-1-(naphthyl-1-sulfonyl)indoline-2-carboxylate

2.4 g of the compound obtained in the previous step are suspended in 30ml of methanol under a nitrogen atmosphere, 26 mg of sodium methylateare added at 0° C., after 10 minutes at room temperature a further 26 mgof sodium methylate are added and, finally, after 45 min, 1 ml of THF isadded in order to achieve total dissolution. Then, after 1 hour, aprecipitate is formed by the addition of dry ice and water. Theprecipitate is filtered off, taken up with ethyl acetate, washed withwater and an aqueous solution of sodium chloride and dried. The oilobtained is chromatographed on silica, the eluents being DCM and thenDCM containing up to 10% of AcOEt; the 2 isomers are separated in thisway.

The compounds contained in each of the fractions are then recrystallizedfrom a DCM/isopropyl ether mixture.

M.p.=155-157° C.: cis isomer

M.p.=141-142° C.: trans isomer

EXAMPLES 3 AND 4

Methyl 5-chloro-3-(2-fluorophenyl )-3-hydroxy-1-(4-nitrophenylsulfonyl)indoline-2-carboxylate, cis somer,trans isomer

A) 5-Chloro-2'-fluoro-2-[(4-nitrophenylsulfonyl)amino ]-benzophenone

A mixture containing 24.9 g of 2-amino-5-chloro-2'-fluorobenzophenoneand 22.1 g of 4-nitrophenylsulfonyl chloride is refluxed for 10 hours inpyridine. It is evaporated to dryness, water and ethyl acetate are thenadded and the ethyl acetate phase is washed with water and an aqueoussolution of sodium chloride, dried over magnesium sulfate and evaporatedunder vacuum. The expected product precipitates on evaporation; it isfiltered off and recrystallized from a DCM/isopropyl ether mixture togive 20 g.

M.p.=155° C.

B)5-Chloro-2'-fluoro-2-[N-(methoxycarbonylmethyl)-N-(4-nitrophenylsulfonyl)amino]benzophenone

5 g of the compound obtained in the previous step are dissolved in 20 mlof DMF at 0° C. under argon, 367 mg of 80% sodium hydride are added, 3.5g of methyl bromoacetate are added after 5 minutes and a further 3.5 gof methyl bromoacetate are added after 1 hour. After 5 hours at roomtemperature, the reaction mixture is poured into iced water and thenextracted 3 times with ethyl acetate and the extract is washed 3 timeswith water and an aqueous solution of sodium chloride and then driedover magnesium sulfate. The product is chromatographed on silica gelusing DCM as the eluent to give 6.1 g of the expected compound, whichsolidifies in methanol.

C) 3 g of the compound obtained in the previous step are suspended in 50ml of methanol and cooled in an ice bath. 330 mg (0.1 equivalent) ofsodium methylate are added and the mixture is stirred for 60 minutes,the temperature being allowed to rise to 10° C. Dry ice and then waterare added, the mixture is extracted 3 times with ethyl acetate and theextract is then washed with water and an aqueous solution of sodiumchloride, dried and evaporated under vacuum. The crude reaction product(6.1 g) is chromatographed on a silica column prepared in DCM.

The 2 isomers are eluted successively with DCM.

The less polar isomer is the cis isomer.

After recrystallization from a DCM/isopropyl ether mixture,m.p.=219-220° C.

The more polar isomer is the trans isomer.

After recrystallization from a DCM/methanol mixture, m.p.=203-204° C.

EXAMPLES 5 AND 6

Methyl 1-(4-aminophenylsul fonyl)-5-chloro-3-(2-fluorophenyl)-3-hydroxyindoline-2-carboxylate transisomer, cis isomer

A)5-Chloro-2'-fluoro-2-[N-(methoxycarbonylmethyl)-N-(4-aminophenylsulfonyl)amino]benzophenone

The5-chloro-2'-fluoro-2-[N-(methoxycarbonylmethyl)-N-(4-nitrophenylsulfonyl)amino]benzophenoneprepared in Example 2, step b, is dissolved in 100 ml of ethyl acetateand 5 ml of methanol and hydrogenated at ordinary pressure for 2 hoursin the presence of 620 mg of 10% palladium-on-charcoal; the existence of3 compounds (starting material, intermediate and expected product) isobserved in TLC. The catalyst is filtered off, the solvent is evaporatedoff and the residue is chromatographed on silica gel. The expectedcompound is eluted with DCM containing 1% of methanol. Afterrecrystallization from DCM/isopropyl ether, m.p=168-170° C.

B) Trans isomer

3.4 g of the compound obtained in the previous step are dissolved in 20ml of methanol and 20 ml of THF at 0 ° C. under nitrogen and 190 mg ofsodium methylate are added. After 60 minutes at 5° C., with stirring,the reaction medium is poured into water and extracted with ethylacetate. A compound crystallizes and is recrystallized from DCMcontaining a small amount of methanol.

M.p.=215-216° C.

This is the trans compound according to a study of the NMR spectrum withNOE.

C) Cis isomer

200 mg of the compound prepared in Example 3 are dissolved in 10 ml ofethyl acetate and 2 ml of methanol and hydrogenated at ordinary pressurefor 3 hours in the presence of 50 mg of 10% palladium-on-charcoal. Thecatalyst is filtered off, the filtrate is evaporated to dryness and theresidue is chromatographed on silica gel, the eluent being DCMcontaining 1% of methanol. The product obtained is recrystallized fromMeOH/isopropyl ether to give 105 mg.

M.p.=186-190° C.

EXAMPLES 7 AND 8

Methyl3-(2-fluorophenyl)-3-hydroxy-5-nitro-1-tosylindoline-2-carboxylate, cisisomer, trans isomer

A) 2'-Fluoro-5-nitro-2-tosylaminobenzophenone

A mixture containing 10 g of 2-amino-5-nitro-2'-fluorobenzophenone and7.5 g of tosyl chloride is refluxed in 50 ml of pyridine for 24 hours.The solvent is evaporated off to dryness, water and ethyl acetate areadded, an insoluble material is filtered off and the organic phase iswashed with a dilute solution of hydrochloric acid, water and an aqueoussolution of sodium chloride and then dried over magnesium sulfate andevaporated. The residue is chromatographed on silica and the expectedproduct is eluted with DCM.

B)2'-Fluoro-2-[N-(methoxycarbonylmethyl)-N-(tosyl)-amino]-5-nitrobenzophenone

4 g of the compound obtained in the previous step are placed in 40 ml ofanhydrous DMF and treated at 0° C. with 320 mg of 80% sodium hydrideand, after 10 minutes, with 6 g of methyl bromoacetate. The mixture isallowed to return to room temperature, water is added and the resultingmixture is extracted with ethyl acetate. The residue obtained afterevaporation of the solvent is purified by chromatography on silica gel.The oil obtained by elution with DCM and then DCM containing up to 2% ofAcOEt solidifies completely.

Elemental analysis: C₂₃ H₁₉ FN₂ O₇ S

calculated % C : 56.79 H : 3.94 N : 5.76

found % C : 56.54 H : 3.88 N : 5.54

C) A suspension containing 1.70 g of the product obtained in theprevious step in 30 ml of methanol is cooled to 10° C. under argon andthen treated with 100 mg of sodium methylate for 45 minutes. A largevolume of water is added, the mixture is extracted with ethyl acetateand the organic phase is washed with water until the washings areneutral, washed with a saline solution, dried over magnesium sulfate andevaporated under vacuum. The residue is chromatographed on silica gel.The less polar compound is eluted with pure DCM to give 700 mg: cisisomer.

M.p.=191-192° C after recrystallization (DCM/isopropyl ether)

The more polar compound is eluted with a DCM/ethyl acetate mixture(95/5, v/v). 650 mg are obtained after recrystallization fromDCM/isopropyl ether.

M.p.=206-207° C.: trans isomer

EXAMPLE 9

Methyl5-amino-3-(2-fluorophenyl)-3-hydroxy-1-tosylindoline-2-carboxylate, cisisomer

450 mg of the cis compound obtained in Example 4 are solubilized in 13ml of an ethyl acetate/methanol mixture (10/3, v/v) and hydrogenated atordinary temperature and pressure for 2 hours in the presence of 100 mgof 10% palladium-on-charcoal. The catalyst is filtered off, the solventis evaporated off and the residue is chromatographed on silica gel usinga DCM/ethyl acetate mixture (1/1, v/v) as the eluent.

A white powder is obtained after trituration in a DCM/isopropyl ethermixture.

M.p.=203° C. (cis isomer)

EXAMPLES 10 AND 11

Methyl5-chloro-3-cyclohexyl-3-hydroxy-1-(4-methoxyphenylsulfonyl)indoline-2-carboxylate,cis isomer, trans isomer

A) 5-Chloro-1-[(4-methoxyphenylsulfonyl)amino]cyclo-hexylphenone

A mixture containing 20 g of 2-amino-5-chloro-phenyl cyclohexyl ketoneand 18 g of 4-methoxyphenylsulfonyl chloride is heated in pyridine at100° C. overnight, the solvent is concentrated, the residue is taken upwith hydrochloric water and extracted with DCM and the extract is driedand concentrated. The residue is recrystallized from an isopropylether/cyclohexane mixture to give 27 g of the expected compound, whichcrystallizes.

M.p.=78-80° C.

B)5-Chloro-1-[N-(methoxycarbonylmethyl)-N-(4-methoxy-phenylsulfonyl)amino]phenylcyclohexyl ketone

The compound obtained in the previous step (27 g) is treated with 2.2 gof sodium hydride in 150 ml of DMF at room temperature under argon for30 minutes. 50 g of methyl bromoacetate are added and the mixture isleft to stand overnight, with stirring. The DMF is evaporated off, theresidue is taken up with water and extracted with DCM and the extract isdried and concentrated. The residue is chromatographed on silica usingDCM as the eluent to give 19.5 g of the expected compound, whichcrystallizes from methanol.

M.p.=115-116° C.

C) The product obtained in the previous step (10 g) is solubilized in350 ml of methanol, and 0.6 g of sodium methylate in 50 ml of methanolis added. After a contact time of 5 minutes, TLC shows that the reactionis complete. The methanol is evaporated off after dry ice has been addedto the medium. The residue is taken up with water and extracted withmethylene chloride and the extract is chromatographed on silica usingmethylene chloride as the eluent.

The first fractions contain the less polar isomer, which isrecrystallized from isopropyl ether.

M.p.=100° C. (cis isomer)

This is followed by the more polar isomer.

M.p.=145° C. (trans isomer)

EXAMPLES 12 AND 13

Methyl 5-chloro-3-hydroxy-3-pentyl-1-tosylindo-line-2-carboxylate, cisisomer, trans isomer

A) 4-Chloro-2-hexanoyl-N-tosylaniline

A mixture containing 15 g of 4-chloro-2-hexanoylaniline and 10.5 g oftosyl chloride is heated in 100 ml of pyridine at 100° C. overnight. Thesolvent is evaporated off, the residue is taken up with hydrochloricwater and extracted with methylene chloride and the extract is dried andconcentrated. The crude reaction product crystallizes from isopropylether to give 14.5 g.

M.p.=78-80° C.

B) 4-Chloro-2-hexanoyl-N-methoxycarbonylmethyl-N-tosylaniline

14 g of the compound obtained in the previous step are treated at 0° C.under argon with 1 g of sodium hydride in DMF. After stirring for 15minutes, 22.5 g of methyl bromoacetate are added and the mixture isstirred overnight at room temperature. After evaporation of the solventand the excess brominated derivative with a vacuum pump, the residue istaken up with water and extracted with methylene chloride, the extractis dried and concentrated and the crude reaction product is thenchromatographed on silica using a DCM/pentane mixture (50/50, v/v) asthe eluent to give 12.1 g of the expected product.

M.p.=68-70° C.

C) 5 g of the compound obtained in the previous step are dissolved at 0°C. in 100 ml of methanol and treated with 600 mg of sodium methylate.After 10 minutes, TLC shows that the starting material has disappeared.Dry ice is added, the solvent is partially evaporated off, the residueis taken up with water and extracted with methylene chloride and theextract is dried and concentrated. The crude reaction product ischromatographed on silica using DCM as the eluent, which separates the 2isomers. The less polar isomer is recrystallized in the cold from anether/cyclohexane mixture to give 0.85 g.

M.p.=95-96° C.: cis isomer

The more polar isomer is recrystallized from isopropyl ether to give 2 gof product.

M.p.=102-104° C.: trans isomer

EXAMPLES 14 AND 15

Methyl1-butylsulfonyl-5-chloro-3-(2-chloro-phenyl)-3-hydroxyindoline-2-carboxylate,cis isomer, trans isomer

A) 2-Butylsulfonamido-2',5-dichlorobenzophenone

11 g of 2',5-dichloroaminobenzophenone and 8.2 g of n-butanesulfonylchloride in 40 ml of pyridine are stirred for 9 days at roomtemperature. The pyridine is evaporated off under vacuum, water isadded, the mixture is extracted with 3 volumes of ethyl acetate and theorganic phase is washed with hydrochloric water and an aqueous solutionof sodium chloride and dried over magnesium sulfate. After evaporationof the solvent, the residue is chromatographed on silica gel, theexpected product being eluted with a pentane/ethyl acetate mixture(90/10, v/v) to give 4.4 g.

B)2-[N-(Butylsulfonyl)-N-(methoxycarbonylmethyl)-amino]-2',5-dichlorobenzophenone

4 g of the compound obtained in the previous step are dissolved in 40 mlof anhydrous DMF at 0° C. under argon, the solution is treated with 320mg of 80% sodium hydride for 15 minutes, 6.5 g of ethyl bromoacetate arethen added over 2 hours and the mixture is left to stand for 6 hours atroom temperature. Water is added, the reaction product is then extractedand the extract is filtered on silica gel using DCM as the eluent togive the expected product in the form of a thick oil.

C) 4.3 g of the compound obtained in the previous step are placed in 50ml of methanol at 0° C. and treated with 54 mg of sodium methylate for 3hours. After the starting material has disappeared (as shown by TLC),the mixture is poured into a large volume of water and extracted with 3volumes of ethyl acetate, the organic phase is washed with water and anaqueous solution of sodium chloride and dried over magnesium sulfate andthe solvent is then evaporated off under vacuum. The residue ischromatographed on silica gel.

The first isomer is eluted with DCM.

M.p.=140-143° C.: cis isomer (recrystallization from DCM/isopropylether)

The second isomer (trans isomer) is eluted with a DCM/isopropyl ethermixture.

M.p.=161-163° C.: trans isomer (recrystallization from DCM/isopropylether)

EXAMPLES 16 AND 17

Methyl5-chloro-3-(2-chlorophenyl)-1-(2,5-dimethoxyphenylsulfonyl)-3-hydroxyindoline-2-carboxylate,cis isomer, trans isomer

A) 2',5-Dichloro-2-(2,5-dimethoxyphenylsulfonamido)-benzophenone

This compound is prepared by the procedure described in the previousExamples.

B)2',5-Dichloro-2-[N-(2,5-dimethoxyphenylsulfonyl)-N-(methoxycarbonylmethyl)amino]benzophenone

8.2 g of the compound prepared in the previous step are dissolved in 60ml of anhydrous DMF at 0° C. under argon, 550 mg of 80% sodium hydrideare added, after 15 minutes 8 g of methyl bromoacetate are then addedand the mixture is stirred for 10 hours at room temperature. Thereaction medium is poured into water and the solid formed is filteredoff and then dissolved in ethyl acetate. The organic phase is washedwith water and an aqueous solution of sodium chloride, dried overmagnesium sulfate and evaporated under vacuum. The solid isrecrystallized from a DCM/isopropyl ether mixture.

M.p.=129-131° C.

C) Methyl5-chloro-3-(2-chlorophenyl)-2-(2,5-dimethoxyphenylsulfonyl)-3-hydroxyindoline-2carbonxylate

The cyclization step can be carried out in the presence of variousreagents.

a) 1 g of the compound obtained in the previous step is dissolved in 10ml of DCM at 0° C., 145 mg of DBU are added and the reaction medium iskept for 24 hours at +5° C. It is poured directly on to a silica columnand eluted with DCM.

The first compound eluted (231 mg) is recrystallized from DCM/isopropylether.

M.p.=168-169° C. (cis isomer)

The trans isomer is eluted next.

M.p.=193-195° C. (recrystallization from DCM/isopropyl ether)

b) 800 mg of the compound obtained in step B are dissolved in 5 ml ofanhydrous THF, 0.8 ml of HMPA is added and the mixture is cooled to -78°C. under an argon atmosphere. 1 ml of a solution of the complex LDA.TFA(1.5M) in cyclohexane is added by syringe; after 45 minutes, a further0.3 ml of LDA is added, water is then added at -78° C. and the mixtureis extracted with ethyl acetate.

NMR analysis of the product obtained shows the existence of the cisisomer (39%) and the trans isomer (61%).

c) 400 mg of the compound obtained in step B are dissolved in 3 ml ofanhydrous THF under argon, the solution is cooled to -78° C. and 0.9 mlof a molar solution of LiHMDS in THF is then added, followed by 0.4 mlof HMPA in 2 ml of THF. After stirring for 60 minutes at -78° C., afurther 0.3 ml of LiHMDS is added, after 10 minutes water is added at-78° C. and the mixture is then extracted with ethyl acetate.

NMR analysis of the product obtained shows the existence of the cisisomer (60%) and the trans isomer (40%).

d) 400 mg of the compound obtained in step B are dissolved in 3 ml ofanhydrous THF, the solution is cooled to -78° C. under argon and 1.8 mlof a solution of KHMDS (0.5M) in 1 ml of toluene and 0.4 ml of HMPA in 1ml of THF are then added. The solution obtained is kept at -78° C. for20 minutes, water is then added and the mixture is extracted with ethylacetate.

NMR analysis of the product obtained shows the existence of the cisisomer (32%) and the trans isomer (68%).

e) 2 ml of THF and 0.4 ml of HMPA are cooled to -70° C. under argon anda molar solution of LiHMDS in 0.9 ml of THF is added; 400 mg of thecompound prepared in step B in 3 ml of THF are then added dropwise.

After one hour at -70° C., water is added and the mixture is thenextracted with ethyl acetate. NMR analysis of the product obtained showsthe existence of the cis isomer (63%) and the trans isomer (37%).

f) 1 g of 1,3-diphenyl-1,1,3,3-tetramethyldisilazane is dissolved in 4ml of anhydrous THF, and 2.2 ml of a 1.6M solution of butyllithium inhexane and 1.8 ml of THF are added at -10° C. under argon.

In a parallel procedure, 400 mg of the compound prepared in step B aredissolved in 3 ml of anhydrous THF at -78° C. under argon and 2.2 ml ofthe solution prepared above are added over 5 minutes, followed by 0.4 mlof HMPA. After 1 hour, a further 0.5 ml of the solution prepared aboveis added, the mixture is then left to stand for 1 hour at -78° C. and,finally, water is added and the mixture is extracted with ether.

NMR analysis of the product obtained shows the existence of the cisisomer (57%) and the trans isomer (43%).

EXAMPLES 18, 19 AND 20

Isopentyl 5-chloro-3-cyclohexyl-3-hydroxy-1-tosylindoline-2-carboxylate,trans isomer, cis isomer, and isopentyl5-chloro-3-cyclohexyl-3-trimethylsilyl-oxy-1-tosylindoline-2-carboxylate,cis isomer

A) 5-Chloro-2-tosylaminophenyl cyclohexyl ketone

This compound is prepared by the procedure described in the previousExamples.

B) 2-[N-(Tosyl)-N-(isopentoxycarbonylmethyl)amino]-5-chlorophenylcyclohexyl ketone

5.7 g of the compound prepared in the previous step are dissolved in 50ml of anhydrous DMF, 420 mg of 80% sodium hydride are added, 12 g ofisopentyl bromoacetate are then added after 15 minutes and the mixtureis stirred for 8 hours at room temperature. After extraction, theextract is chromatographed on silica gel and an oil is eluted withmixtures from pentane/DCM (20/80, v/v) to pure DCM.

C) Isopentyl5-chloro-3-cyclohexyl-3-hydroxy-1-tosyl-indoline-2-carboxylate, transisomer

1.6 g of the compound obtained in the previous step are dissolved in 10ml of anhydrous 3-methylbutanol. The solution is cooled to 0° C., 7 mgof sodium methylate are added and the mixture is then brought back toordinary temperature over 150 minutes. Dry ice and water are added, themixture is extracted by decantation and the extract is washed with waterand an aqueous solution of sodium chloride and dried over magnesiumsulfate. The solvent is evaporated off under vacuum and the residue isthen chromatographed on silica gel. A mixture of 2 isomers (1.6 g) iseluted with DCM and recrystallized from a DCM/isopropyl ether mixture:SR 47275 (trans isomer).

D) Isopentyl5-chloro-3-cyclohexyl-3-trimethylsilyl-oxy-1-tosylindoline-2-carboxylate,cis isomer

The mother liquors from crystallization of the trans isomer (980 mg) aredissolved under argon in 8 ml of hexamethyldisilazane in the presence of100 mg of imidazole and the mixture is heated at 120° C. The reaction isfollowed by TLC on silica gel using DCM as the eluent.

A product of low polarity appears after 1 hour and a second compound,which is slightly more polar than the previous one, appears after onenight. The solvent is evaporated off to dryness under vacuum and theresidue is chromatographed on silica gel. The less polar compound iseluted with a DCM/pentane mixture (50/50, v/v) to give 304 mg, which arerecrystallized from a DCM/isopropyl ether mixture.

M.p.=118-121° C.

E) Isopentyl5-chloro-3-cyclohexyl-3-hydroxy-1-tosylindoline-2-carboxylate, cisisomer

2.4 mg of solid sodium hydroxide are added to a suspension of the motherliquors of the cis isomer isolated above (220 mg) in 1 ml of water and 3ml of THF. After 3 hours, water is added, the THF is partiallyevaporated off and the mixture is extracted under vacuum at roomtemperature by the customary methods. The residue is chromatographed onsilica using a DCM/pentane mixture (95/5, v/v) as the eluent. Accordingto the NMR spectrum, 87% of the compound obtained is in the cis form.

EXAMPLE 21

Butyl 5-chloro-3-cyclohexyl-3-hydroxy-1-tosylindoline-2-carboxylate

This compound is prepared by the reaction of butyl bromoacetate with5-chloro-2-tosylaminophenyl cyclohexyl ketone, followed by cyclizationin the presence of sodium methylate in butanol.

The compound formed is the trans isomer.

M.p.=115° C.

EXAMPLES 22 AND 23

Methyl5-chloro-3-(2-chlorophenyl)-3-hydroxy-2-methyl-1-tosylindoline-2-carboxylate,cis isomer, trans isomer

A mixture containing 0.5 g of2',5-dichloro-2-[N-(1-methoxycarbonylethyl)-N-(tosyl)amino]benzophenone,0.1 g of sodium methylate and 2 ml of DMF is stirred for 20 hours atroom temperature under nitrogen. It is concentrated under vacuum, theresidue is taken up with water and the precipitate is filtered off andwashed with water. The residue is chromatographed on silica using DCM asthe eluent to give 60 mg of the cis isomer and 250 mg of the transisomer.

EXAMPLE 24

Methyl5-chloro-3-(2-chlorophenyl)-1-(4-cyanophenylsulfonyl)-3-hydroxyindoline-2-carboxylate,cis isomer

A) 2-[N-(4-Cyanophenylsulfonyl)amino]-2',5-dichlorobenzophenone

10 g of 2-amino-2',5-dichlorobenzophenone and 7.7 g of4-cyanophenylsulfonyl chloride are heated in pyridine at 100° C. for 48hours in the presence of 4.6 g of DMAP, the mixture is evaporated todryness, water and ethyl acetate are added, the organic phase is washedwith dilute hydrochloric water, water and an aqueous solution of sodiumchloride and dried over magnesium sulfate and the solvent is evaporatedoff under vacuum. The precipitate formed is filtered off and thenrecrystallized twice from a DCM/isopropyl ether mixture to give theexpected product.

M.p.=172-173° C.

B)2-[N-(4-Cyanophenylsulfonyl)-N-(methoxycarbonylmethyl)amino]-2',5-dichlorobenzophenone

10 g of the compound obtained in the previous step are dissolved in 70ml of DMF at 0° C. under argon, 740 mg of 80% sodium hydride are thenadded and 14 g of methyl bromoacetate are added after 15 minutes. After24 hours, water is added, the aqueous phase is decanted, the solidobtained is extracted with AcOEt and the organic phase is washed withwater and an aqueous solution of sodium chloride, dried over magnesiumsulfate and evaporated under vacuum to give the expected product, whichis recrystallized from DCM/isopropyl ether.

M.p.=186-188° C.

C) 2 g of the previous compound are suspended at 0° C. in 40 ml of anMeOH/THF mixture (1/1, v/v) and treated with 100 mg of sodium methylate.After 3 hours at ordinary temperature, total dissolution is observed.The solvents are partially evaporated off under vacuum, a large amountof water is added and the mixture is extracted with ethyl acetate. Theextract is washed with water and an aqueous solution of sodium chloride,dried over magnesium sulfate and evaporated under vacuum. The residue ischromatographed on silica gel. The 2 isomers are successively elutedwith methylene chloride.

The less polar isomer is recrystallized from DCM/isopropyl ether.

M.p.=222-223° C. (cis isomer)

EXAMPLES 25 AND 26

Methyl5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline-2-carboxylate,trans isomer, cis isomer

A) 2',5-Dichloro-2-(3,4-dimethoxyphenylsulfonamido)-benzophenone

5.6 g of 2-amino-2',5-dichlorobenzophenone and 5 g of3,4-dimethoxyphenylsulfonyl chloride are heated in pyridine overnight at100° C. The pyridine is evaporated off to dryness, water and ethylacetate containing a small amount of DCM are added and the mixture isextracted. After washing several times with water and drying over sodiumsulfate, the extract is evaporated under vacuum and 7.7 g of theexpected product are recrystallized from a DCM/AcOEt mixture.

M.p.=164° C.

B)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(methoxycarbonylmethyl)amino]benzophenone

7.2 g of the compound obtained in the previous step are dissolved inanhydrous DMF at 0° C. under nitrogen. 500 mg of sodium hydride areadded, followed after 10 minutes by 9.5 g of ethyl bromoacetate. After 1night, excess water is added and the precipitate obtained is filteredoff. It is dissolved in DCM, the solution is dried over magnesiumsulfate and the solvent is evaporated off. 7.7 g of the expected productare recrystallized from a DCM/isopropyl ether mixture.

M.p.=164 C.

C) Trans isomer

A suspension of 7 g of the product obtained in the previous step in 90ml of methanol containing 2 ml of THF is cooled to 0° C. under nitrogenand treated with 720 mg of sodium methylate. After 2 hours at ordinarytemperature, the unreacted starting material is filtered off, a largevolume of water and dry ice are added and the mixture is extracted withethyl acetate. 4 products appear in TLC. The most abundant product isrecrystallized twice from a DCM/isopropyl ether mixture.

M.p.=184-185° C.: trans isomer

D) Cis isomer

1.3 g of the compound obtained in step B are dissolved at 0° C. in 13 mlof DCM in the presence of 180 mg of DBU. After stirring overnight, thereaction medium is poured directly on to a silica column prepared in DCMand the mixture of compounds resulting from cyclization is thusseparated by elution with DCM. Chromatography is then carried out onalumina using a DCM/isopropyl ether mixture (70/30, v/v) as the eluent.The cis isomer is thus isolated.

NMR spectrum at 200MHz in DMSO at T=370° K.:

    ______________________________________                                        Delta      Appearance Integration Assignment                                  ______________________________________                                        2.50                              DMSO                                        3.15       s          3 H         CO.sub.2 CH.sub.3                           3.80       s          3 H         OCH.sub.3                                   3.85       s          3 H         OCH.sub.3                                   5.10       s          1 H         CH                                          6.50       s          1 H         OH                                          7.00 to 7.80                                                                             m          10 H        aromatic                                                                      protons                                     ______________________________________                                    

EXAMPLES 27, 28, 29 AND 30

Benzyl5-chloro-3-(2-chlorophenyl)-3-hydroxy-1-p-tosylindoline-2-carboxylate,trans isomer, cis isomer, and5-chloro-3-(2-chlorophenyl)-3-hydroxy-1-p-tosylindoline-2-carboxylicacid, trans isomer, cis isomer

A)2',5-Dichloro-2-[N-(tosyl)-N-(benzyloxycarbonylmethyl)amino]benzophenone

20 g of 2',5-dichloro-2-N-tosylaminobenzophenone (prepared by thecustomary method) and 1.6 g of sodium hydride are reacted in 100 ml ofDMF. After stirring for 15 minutes, 34 g of benzyl bromoacetate areadded and the mixture is left to stand overnight at room temperature.The DMF is evaporated off, the residue is taken up with water andextracted with methylene chloride, and then dried and concentrated. Thecrude product obtained is chromatographed on silica gel using DCM as theeluent. The 14.39 g of product obtained are recrystallized fromisopropyl ether.

M.p.=99-101 C.

B) Benzyl5-chloro-3-(2-chlorophenyl)-3-hydroxy-1-p-tosylindoline-2-carboxylate,trans isomer

1 g of the compound obtained in the previous step is treated at -78° C.with 1.2 ml of concentrated LDA (1.5M) in cyclohexane. After 3 hours,the mixture is taken up with water and extracted with DCM and theextract is dried and concentrated. The crude reaction product ischromatographed on silica gel using DCM as the eluent and the mixture of2 isomers is separated. The more polar isomer is recrystallized twicefrom a DCM/isopropyl ether mixture to give 600 mg of trans isomer.

M.p.=168-169° C. (recrystallization from DCM/isopropyl ether)

C) Benzyl5-chloro-3-(2-chlorophenyl)-3-hydroxy-1-p-tosylindoline-2-carboxylate,cis isomer

2 g of the compound prepared in step A are dissolved in DCM at 0° C. and540 mg of DBU are added. After 20 minutes at 0° C., a potassium sulfatesolution and water are added, the mixture is then extracted and theextract is dried and concentrated. Chromatography on silica using DCM asthe eluent gives 450 mg of the less polar product (cis isomer) and 700mg of the more polar product (trans isomer).

The cis isomer is obtained in the form of a

Elemental analysis:

calculated % C : 61.27 H : 4.05 N : 2.46

found % 61.29 4.20 2.48

D) 5-Chloro-3-(2-chlorophenyl)-3-hydroxy-1-p-tosyl-indoline-2-carboxylicacid, trans isomer

500 mg of the trans isomer of the compound prepared in step B aredissolved in 300 ml of ethyl acetate in the presence of 100 mg ofpalladium-on-charcoal. The product crystallizes after 10 min ofhydrogenolysis. The palladium is filtered off and the crystals are thensolubilized with hot DMF. The DMF is concentrated and the residue istaken up with a large volume of THF. The mixture is concentrated,methanol is added and the product crystallizes to give 175 mg of theexpected product (trans isomer).

    ______________________________________                                        NMR:                                                                          Delta   Appearance Integration Assignment                                     ______________________________________                                        2.44    s          3 H         CH.sub.3 (tosyl)                               4.87    s          1 H         H6 (2-chlorophenyl)                            6.74    d          1 H         H4 (indole)                                    6.98    s          1 H         OH                                             7.28-7.53                                                                             m          7 H         aromatic protons                               7.88    d          2 H         OH                                                     (J = 8.6 Hz)           H2, H6 (tosyl)                                 ______________________________________                                    

In the same way, the cis isomer of the acid is prepared byhydrogenolysis of the benzyl ester obtained in step C.

M.p.=209-212° C.

EXAMPLE 31

5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline-2-carboxylicacid, cis isomer

This acid is prepared by the procedure described in the previous Examplevia the benzyl ester of said acid.

M.p.=130-132° C.

Methyl esters of formula (I) were prepared by analogous procedures. Theyare described in Table 1 below.

                  TABLE 1                                                         ______________________________________                                         ##STR26##                     (I)                                            For each compound of formula (I) having the substituents                      R.sub.1, R.sub.2 and R.sub.5 in the Table below, the cis isomer               is indicated and then the trans isomer, unless stated otherwise.              Ex-                                                                           ample R.sub.1  R.sub.2   R.sub.5  M.p. °C. Solvent                     ______________________________________                                        32    H        phenyl    p-tolyl  154                                         33                                170                                         34    5-Cl     cyclopentyl                                                                             p-tolyl  187-190                                                                       DCM/MeOH                                    35                                153-157                                                                       DCM/isopropyl                                                                 ether                                       36    5-Cl     cyclohexyl                                                                              p-tolyl  180                                                                           ether/cyclohexane                           37                                144                                                                           ether/cyclohexane                           38    5-Cl     cyclohexyl                                                                              2-naphthyl                                                                             177                                                                           MeOH                                        39                                150                                                                           ether/cyclohexane                           40    5-Cl     isopropyl p-tolyl  158                                                                           DCM/isopropyl                                                                 ether                                       41                                172                                                                           DCM/isopropyl                                                                 ether                                       42    5-Cl     2-F-phenyl                                                                              p-tolyl  165-166                                                                       DCM/isopropyl                                                                 ether                                       43                                212-213                                                                       DCM/isopropyl                                                                 ether                                       44    5-Cl     phenyl    p-tolyl  206                                         (*)                               DCM/isopropyl                                                                 ether/MeOH                                  45                                193-194                                                                       AcOEt/MeOH                                  46    5-Cl     cycloheptyl                                                                             p-tolyl  170-172                                                                       isopropyl ether                             47                                154-155                                     48    5-Cl     2-Cl-phenyl                                                                             p-tolyl  174                                         49                                255                                         50    5-Cl     cyclohexyl                                                                              4-dimethyl-                                                                            184-185                                                              aminophenyl                                          51                                198-200                                                                       DCM/isopropyl                                                                 ether                                       52    5-Cl     cyclohexyl                                                                              2,4,6-tri-                                                                             139-142                                                              methylphenyl                                                                           DCM/isopropyl                                                                 ether                                       53                                200-203                                                                       DCM/isopropyl                                                                 ether                                       54    5-Cl     cyclohexyl                                                                              n-butyl  150-153                                                                       MeOH/isopropyl                                                                ether                                       55    5-Cl     2-Cl-phenyl                                                                             2-CF.sub.3 -phenyl                                                                     216                                         56                       2-CF.sub.3 -phenyl                                                                     242                                         57    5-Cl     2-Cl-phenyl                                                                             4-benzyloxy-                                                                           166                                                                  phenyl   DCM/isopropyl                                                                 ether                                       58                                195                                                                           DCM/isopropyl                                                                 ether                                       59    5-Cl     2-Cl-phenyl                                                                             4-Cl-phenyl                                                                            174                                         60                                230                                         61    5-Cl     4-Cl-phenyl                                                                             p-tolyl  224                                         62                                186                                                                           EtOH                                        63    5-Cl     2-CH.sub.3 -                                                                            p-tolyl  168                                                        phenyl                                                         64                                238                                                                           AcOEt                                       65    5-Cl     2-Cl-phenyl                                                                             4-OH-phenyl                                                                            NMR(**)                                     66                                163                                                                           MeOH/isopropyl                                                                ether                                       67    5-Cl     2-Cl-phenyl                                                                             3-Cl-phenyl                                                                            175                                         68                                186                                         69    5-Cl     2-Cl-phenyl                                                                             m-tolyl  173                                         70                                229                                         71    5-Cl     2-methoxy-                                                                              p-tolyl  165                                                        phenyl                                                         72                                240                                         73    5-Cl     3-Cl-phenyl                                                                             p-tolyl  137                                         74                                210                                         75    5-Cl     2-methyl- 3,4-diCl-                                                                              196                                                        phenyl    phenyl                                               76                                175                                         77    5-Cl     2-Cl-phenyl                                                                             3-methoxy-                                                                             132                                         cis                      phenyl                                               78    5-Cl     2-Cl-phenyl                                                                             2,3,4-tri-                                                                             207                                                                  methoxy-                                                                      phenyl                                               79                                183                                         80    5-Cl     2-Cl-phenyl                                                                             4-butoxy-                                                                              124-125                                                              phenyl   hexane                                      81                                190-192                                                                       MeOH/isopropyl                                                                ether                                       82    5-Cl     2-Cl-phenyl                                                                             4-trifluoro-                                                                           170                                                                  methoxy-                                                                      phenyl                                               83                                166                                         84    5-Br     2-F-phenyl                                                                              3,4-di-  162-164                                                              methoxy-                                                                      phenyl                                               85                                162-165                                                                       DCM/isopropyl                                                                 ether                                       86    5-Cl     2-Cl-phenyl                                                                             phenyl   148                                                                           isopropyl ether                             87                                230                                                                           DCM/isopropyl                                                                 ether                                       88    5-Cl     2-Cl-phenyl                                                                             4-methoxy-                                                                             173                                                                  phenyl   hexane/isopropyl                                                              ether                                       89                                217                                                                           hexane/isopropyl                                                              ether                                       90    5-Br     2-Cl-phenyl                                                                             3,4-di-  160-162                                                              methoxy-                                                                      phenyl                                               91                                199                                         92    5-Cl     2-Cl-phenyl                                                                             4-ethoxy-                                                                              174                                                                  phenyl   hexane/isopropyl                                                              ether                                       93                                186                                                                           hexane/isopropyl                                                              ether                                       94    2-CH.sub.3 O                                                                           2-Cl      p-tolyl  215                                         trans                                                                         95    5-CH.sub.3                                                                             2-Cl-phenyl                                                                             p-tolyl  165                                         96                                216                                                                           EtOH                                        97    5-CF.sub.3                                                                             2-CF.sub.3 -                                                                            p-tolyl  189                                                        phenyl                                                         98                                202                                         99    5-Cl     2-CF.sub.3 -                                                                            p-tolyl  166                                                        phenyl                                                         100                               205                                         101   5-Cl     2-Cl-phenyl                                                                             3-methoxy-                                                                             206.5                                       trans                    phenyl                                               102   5-Cl     2-Cl-phenyl                                                                             4-CF.sub.3 -phenyl                                                                     191                                         103                               180                                         ______________________________________                                         (*)For this compound, the silylated derivative (VII) was prepared: cis        isomer, m.p. = 176-178° C.                                             (**)Example 65: NMR spectrum at 200 MHz in DMSO at T = 380° K.:   

    Delta   Appearance  Integration                                                                              Assignment                                     ______________________________________                                        2.45                           DMSO                                           3.10    s           3H         CO.sub.2 CH.sub.3                              5.00    s           1H         CH                                             6.30    s           1H         OH                                             6.80-7.80                                                                             m           11H        aromatic protons                               ______________________________________                                    

EXAMPLES 104 AND 105

N,N-Dimethyl-5-chloro-3-cyclohexyl-3-hydroxy-1-tosylindoline-2-carboxamide,trans isomer cis isomer

A) 5-Chloro-2-tosylaminophenyl cyclohexyl ketone

This compound is the one prepared in Example 18, step A.

B) Dimethylbromoacetamide

A solution containing 56 g of bromoacetyl bromide in 100 ml of DCM iscooled to 0° C. and gaseous dimethylamine is bubbled into the mediumuntil it becomes basic. The mixture is filtered and dried and the crudeamide is concentrated to give an oil (22 g).

C) 2-[N-(Tosyl)-N-(dimethylcarbamoylmethyl)amino]-5-chlorophenylcyclohexyl ketone

4.3 g of 5-chloro-2-tosylaminophenyl cyclohexyl ketone are placed in 20ml of DMF in the presence of 360 mg of 80% sodium hydride, after 15minutes at RT 5.4 g of the compound prepared in step B are added and themixture is stirred overnight at RT. The reaction medium is poured intowater and the precipitate is filtered off and then taken up with DCM,dried and concentrated. The expected product crystallizes from isopropylether.

m=3.9 g

M.p.=184-187° C.

N,N-Dimethyl-5-chloro-3-cyclohexyl-3-hydroxy-1-tosylindoline-2-carboxamide,trans isomer

1.5 g of the compound obtained in the previous step are cooled to -78°C. in 20 ml of anhydrous THF, 2.3 ml of a 1.5M solution of LDA incyclohexane are added and the mixture is stirred for 2 hours at -78° C.It is poured into water and extracted with DCM and the extract is driedand concentrated. The crude product obtained is chromatographed onsilica; an AcOEt/DCM mixture (10/90, v/v) elutes a compound which isshown by NMR to be the trans isomer. It is recrystallized from anisopropyl ether/DCM mixture.

M.p.=179-182° C.

E)N,N-Dimethyl-5-chloro-3-cyclohexyl-3-hydroxy-1-tosylindoline-2-carboxamide,cis isomer

1.5 g of the product obtained in step C are treated with 950 mg of DBUin 10 ml of DCM for 24 hours at RT. The reaction medium is thenchromatographed on silica using a DCM/AcOEt mixture (95/5, v/v) as theeluent to give the other isomer (cis isomer). It is recrystallized fromisopropyl ether.

m=120 mg

M.p.=152-155° C.

EXAMPLES 106 AND 107

N,N-Dimethyl-5-chloro-3-(2-chlorophenyl)-3-hydroxy-1-tosylindoline-2-carboxamide,trans isomer, cis isomer.

A) 5,2'-Dichloro-2-tosylaminobenzophenone

This compound is prepared by the customary method.

B)2-[N-(Tosyl)-N-(dimethylcarbamoylmethyl)amino]-5,2'-dichlorobenzophenone

8.4 g of 5,2'-dichloro-2-tosylaminobenzophenone are dissolved in 40 mlof DMF and treated with 0.7 g of 80% sodium hydride; after 15 minutes,10 g of dimethylbromoacetamide, prepared in Example 1, are added and themixture is stirred overnight at RT. The reaction medium is poured intowater, the precipitate formed is filtered off and taken up with DCM andthe solution is dried and concentrated. 9.2 g of the expected productare obtained after crystallization from isopropyl ether.

M.p.=154-157° C.

C)N,N-Dimethyl-5-chloro-3-(2-chlorophenyl)-3-hydroxy1-tosylindoline-2-carboxamide,trans isomer

1.5 g of the compound obtained in the previous step are treated at -78C., in 100 ml of anhydrous THF, with 2.6 ml of a 1.5 M solution of LDAin cyclohexane for 3 hours. The mixture is poured into water andextracted with DCM and the extract is dried and concentrated. Theresidue is chromatographed on silica using a DCM/AcOEt mixture (94/6,v/v) as the eluent. A small amount of the less polar compound iscollected and the more polar compound is then eluted: trans isomer.

It is recrystallized from a DCM/isopropyl ether mixture.

M.p.=232-233° C.

D)N,N-Dimethyl-5-chloro-3-(2-chlorophenyl)-3-hydroxy1-tosylindoline-2-carboxamide,cis isomer

1.5 g of the compound prepared in step B are refluxed in DCM for 24hours in the presence of 900 mg of DBU. The mixture is chromatographedon a silica column using a DCM/AcOEt mixture (95/5, v/v) as the eluent.190 mg of the expected product are obtained after recrystallization fromisopropyl ether.

M.p.=220-221° C. E) The compound of step B (1.0 g) is dissolved inacetonitrile (25 ml), and 109 mg of sodium hydroxide in 2 ml of waterare added. The medium is heterogeneous; it is stirred violently at 45°C. for 1 hour, using turbine and compressed air, either in the presenceof 110 mg of benzyltriethylammonium chloride or without the addition ofthis reagent.

After extraction, the product obtained in the form of a mixture of the 2isomers, cis and trans, is determined. The ratio of the 2 isomersobserved by NMR at 360° K. in DMSO is 1/1.

EXAMPLE 108

N,N-Dimethyl-1-(4-allyloxyphenylsulfonyl)-5-chloro-3-(2-chlorophenyl)-3-hydroxyindoline-2-carboxamide, cisisomer

A) Sodium 4-allyloxyphenylsulfonate

30 g of sodium phenylsulfonate are dissolved in 60 ml of ethanol and 50ml of 15% sodium hydroxide, 20 g of allyl bromide are added and themixture is refluxed for 48 hours. The ethanol is concentrated and theprecipitate obtained is filtered off and then dried under vacuum in thepresence of phosphorus pentoxide to give 23.3 g of the expected product.

B) 4-Allyloxyphenylsulfonyl chloride

The product obtained in the previous step (23.3 g) is treated overnightwith 24 g of phosphorus pentachloride under reflux in 300 ml of DCM. Themedium is filtered and concentrated to give an oil (16.5 g).

C) 2-[N-(4-Allyloxyphenylsulfonyl)amino]-2',5-dichlorobenzophenone

The sulfonyl chloride obtained in the previous step is added to 19 g of2', 5-dichloro-2-aminobenzophenone in 200 ml of pyridine. After onenight at room temperature, the pyridine is concentrated, the residue istaken up with hydrochloric water and extracted with DCM and the extractis dried and concentrated. The crude product is chromatographed onsilica and a DCM/pentane mixture (50/50, v/v) elutes the expectedproduct, which is crystallized from a DCM/isopropyl ether mixture togive 8.5 g of the expected product.

M.p.=96°-97° C.

D)2-[N-(4-Allyloxyphenylsulfonyl)-N-(N',N'-dimethylcarbamoylmethyl)amino]-2',5-dichlorobenzophenone

4 g of the product obtained in the previous step are dissolved in 20 mlof DMF under nitrogen, 310 mg of 80% sodium hydride are added, themixture is stirred for 15 minutes at RT and 3.1 g ofbromo-N,N-dimethylacetamide are then added. After one night at RT, themedium is poured into water, the product is filtered off and taken upwith DCM, the solution is dried and concentrated and the residue is thencrystallized from a DCM/isopropyl ether mixture to give 4 g of theexpected product, which is finally recrystallized from the same solventmixture.

M.p.=133°-135° C.

E)N,N-Dimethyl-1-(4-allyloxyphenylsulfonyl)-5-chloro-3-(2-chlorophenyl)-3-hydroxyindoline-2-carboxamide,cis isomer

3.8 g of the product obtained in the previous step are treated at 30° C.with 1.8 g of DBU in 20 ml of DCM for 3 days. The medium ischromatographed on alumina and DCM elutes the less polar compound, whichis recrystallized from a DCM/isopropyl ether mixture to give m=840 mg.

M.p.=181°-182° C.

EXAMPLE 109

N-Benzyl-N-methyl-5-chloro-3-(2-chlorophenyl)-3-hydroxy-1-(3,4-dimethoxyphenylsulfonyl)indoline-2-carboxamide,cis isomer

A) N-Methyl-N-benzylbromoacetamide

At 0° C., a solution of 10 g of bromoacetyl bromide in 20 ml of DCM isadded to a solution of 6 g of methylbenzylamine and 5 g of triethylaminein 50 ml of DCM. After one night at RT, ether is added, the precipitateformed is filtered off and the filtrate is concentrated to give 12 g ofthe expected product in crude form.

B) 2',5-Dichloro-2-(3,4-dimethoxyphenylsulfonamido)-benzophenone

This compound was prepared in Example 25 step A.

C)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(N'-methyl-N'-benzylcarbamoylmethyl)amino]benzophenone

5.5 g of the compound described in step B are dissolved in 30 ml of DMFand treated with 400 mg of sodium hydride. After 15 minutes, 12 g of thebrominated derivative prepared in step A are added and the mixture isstirred at RT for 24 hours. The DMF is evaporated off, the residue istaken up with water and extracted with DCM and the extract is dried andconcentrated. The crude product is chromatographed on silica and theexpected product is eluted with DCM.

m=2.1 g

M.P.=148°-150° C.

D)N-Benzyl-N-methyl-5-chloro-3-(2-chlorophenyl)-3-hydroxy-1-(3,4-dimethoxyphenylsulfonyl)indoline-2-carboxamide,cis isomer

The 2.1 g of product obtained in the previous step are treated with 1 gof DBU in 20 ml of DCM for 3 days. The reaction medium is poured on toan alumina column and DCM elutes the less polar isomer (870 mg) in theform of an oil. After drying, a foam is obtained which is characterizedby NMR:

2.81 ppm : s : 3 H : N--CH₃

3.60 ppm : m : 8 H : 2OCH₃ +N--CH₂ --C₆ H₅

5.35 ppm : s : 1 H : CH (2-indoline)

6.20-7.80 ppm : m : 16 H : aromatic protons+OH

EXAMPLES 110 AND 111

5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-pyrrolidinocarbonylindoline,cis isomer, trans isomer

This compound is prepared by the customary procedure by the reaction ofpyrrolidine bromoacetamide with2-(3,4-dimethoxyphenylsulfonamido)-5,2'-dichlorobenzophenone and thencyclization of the resulting product with DBU in chloroform. A productis eluted on an alumina column with DCM/AcOEt (90/10, v/v); it is thecis isomer.

M.p.=237° C.

AcOEt elutes the trans isomer, which is then recrystallized from AcOEt.

M.p.=230° C.

EXAMPLE 112

5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline-2-carboxamide,trans isomer

A) 2',5-Dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenone

114 g of 2-amino-5,2'-dichlorobenzophenone and 100 g of3,4-dimethoxyphenylsulfonyl chloride are mixed in 300 ml of pyridine.After 4 days at RT, the excess pyridine is evaporated off, the residueis taken up with hydrochloric water and extracted with DCM and theextract is dried and concentrated. The expected product thencrystallizes from a DCM/isopropyl ether mixture.

m=181 g

M.p.=159°-161° C.

B)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(benzyloxycarbonylmethyl)amino]benzophenone

172 g of the product prepared above are dissolved in 800 ml of DCM andcooled to 0° C. 11.7 g of 80% sodium hydride are added gradually undernitrogen, 256 g of benzyl bromoacetate are then added after 30 minutesand the mixture is stirred for 24 hours at RT. The DMF is evaporatedoff, the residue is taken up with water and extracted with DCM and theextract is dried and concentrated. The expected product crystallizesfrom isopropyl ether and is then recrystallized from a DCM/isopropylether mixture.

m=136.5 g

M.p.=102°-104° C.

C) Benzyl5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline-2-carboxylate,trans isomer

3 g of the product obtained in the previous step are treated with 740 mgof TBD in 20 ml of DCM at RT for 1 hour. The reaction medium ischromatographed on silica and DCM elutes the expected compound in theform of the trans isomer, which is the only isomer formed by thecyclization reaction.

The compound obtained is recrystallized from a DCM/isopropyl ethermixture.

m=2 g

M.p.=190°-192° C.

D)5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline-2-carboxylicacid, trans isomer

The benzyl ester obtained in the previous step, in 50 ml of AcOEt, istreated with hydrogen for 30 minutes in the presence of 100 mg of 10%Pd/C. The reaction medium is filtered on Celite®, the material on thefilter is washed with hot methanol and the filtrate is concentrated. Theexpected product crystallizes from a DCM/isopropyl ether mixture.

m=1.5 g

M.p.=218°-221° C.

E)5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline-2-carboxamide,trans isomer

180 mg of the compound obtained in the previous step, in 15 ml of DCM,are treated with 140 mg of BOP in the presence of a sufficient amount ofDIPEA to solubilize the acid. After 15 minutes, gaseous ammonia isintroduced for 10 minutes. The medium is poured into a saturatedsolution of sodium hydrogencarbonate and extracted and the extract isdried and then concentrated. The crude product is chromatographed onsilica using a DCM/AcOEt mixture (80/20, v/v) as the eluent to give theexpected compound, which is then recrystallized from a DCM/isopropylether mixture.

m=63 mg

M.p.=183°-185° C.

EXAMPLES 113 AND 114

N-Isopentyl-5-chloro-3-cyclohexyl-3-hydroxy-1-tosylindoline-2-carboxamide,cis isomer, trans isomer

A) 2-(N-tosylamino)-5-chlorophenyl cyclohexyl ketone is prepared by thecustomary method.

B) 2-[N-(N'-Isopentylcarbamoylmethyl)-N-(tosyl)amino]-5-chlorophenylcyclohexyl ketone

7.2 g of the compound obtained above in 130 ml of DMF are cooled to 0°C. and placed under argon, 1.1 equivalents of sodium hydride are addedand the mixture is allowed to return to RT. 15.2 g ofN-isopentyl-2-bromoacetamide are then added and the mixture is stirredovernight at RT. The DMF is evaporated off, the residue is taken up withwater and extracted with DCM and the extract is dried and concentrated.The crude product is chromatographed on silica using an ether/pentanemixture (70/30, v/v) as the eluent.

C)N-Isopentyl-5-chloro-3-cyclohexyl-3-hydroxy-1-tosyl-indoline-2-carboxamide,mixture of isomers

2.1 equivalents of LDA are added to 3 g of the above product in 50 ml ofanhydrous THF at -20° C. and the temperature is then kept at +4° C. for30 minutes. The medium is poured into a saturated solution of ammoniumchloride and extracted and the extract is dried and concentrated.Chromatography on silica using methylene chloride as the eluent givesthe expected product in the form of a mixture of 2 isomers.

m=2 g

D)N-Isopentyl-5-chloro-3-cyclohexyl-3-trimethylsilyloxy-1-tosylindoline-2-carboxamide

1 g of the product obtained above is heated at 100° C. in 5 g of HMDSfor 12 hours under argon in the presence of 0.1 g of imidazole. Themedium is evaporated, the residue is taken up with DCM and the solutionis chromatographed on silica. DCM successively elutes the less polarisomer, which is recrystallized from isopropyl ether:

m=345 mg

M.p.=137°-138° C. and then the more polar isomer, which isrecrystallized from isopropyl ether:

m=165 mg

M.p.=175°-176° C.

E)N-Isopentyl-5-chloro-3-cyclohexyl-3-hydroxy-1-tosylindoline-2-carboxamide,cis isomer

150 mg of the less polar isomer obtained above are treated with 10 mg ofsodium hydroxide at 0° C. in 5 ml of THF and 2 ml of water for 3 hours.The mixture is taken up with water and extracted with DCM and theextract is dried and concentrated. The crude product is recrystallizedfrom a DCM/isopropyl ether mixture.

m=120 mg

M.p.=189°-191° C.

F)N-Isopentyl-5-chloro-3-cyclohexyl-3-hydroxy-1-tosylindoline-2-carboxamide,trans isomer

150 mg of the more polar isomer obtained in step D are treated with 10mg of sodium hydroxide in 5 ml of THF and 2 ml of water for 2 hours atRT. The mixture is taken up with water and extracted with DCM and theextract is dried and concentrated. The expected product isrecrystallized from a DCM/isopropyl ether mixture.

m=65 mg

M.p.=195°-196° C.

The compounds according to the invention which are described in Table 2below were prepared by following the procedure given in the Examplesdescribed above:

                                      TABLE 2                                     __________________________________________________________________________     ##STR27##                                                                    For each compound of formula (I) having the substituents R.sub.1,             R.sub.2, (R'.sub.5).sub.p'                                                    and NR.sub.6 R.sub.7 in the Table below, the cis isomer is indicated and      then the                                                                      trans isomer, unless stated otherwise.                                         Ex.                                                                               R.sub.1                                                                            R.sub.2   (R.sub.13).sub.p'                                                                     ##STR28##      M.p. °C. crystallization                                               solvent                            __________________________________________________________________________    115 5-Cl 2-Cl-phenyl                                                                             3,4-dimethoxy                                                                         N(CH.sub.3).sub.2                                                                            201                                                                           DCM/isopropyl ether                 116                                       222                                                                           DCM/isopropyl ether                 117 5-Cl cyclohexyl                                                                              4-CH.sub.3                                                                            NHCH.sub.3     224-225                                                                       DCM/isopropyl ether                 118                                       141-148                                                                       DCM/isopropyl ether                 119 5-Cl 2-Cl-phenyl                                                                             3,4-dimethoxy                                                                         NHCH.sub.3     148                                 trans                                     DCM/isopropyl ether                 120 5-Br 2-F-phenyl                                                                              3,4-dimethoxy                                                                         N(CH.sub.3).sub.2                                                                            165                                                                           DCM/isopropyl ether                 121                                       214                                                                           DCM/isopropyl ether                 122 5-Cl 2-Cl-phenyl                                                                             2,5-dimethoxy                                                                         N(CH.sub.3).sub.2                                                                            140-142                             cis                                       DCM/isopropyl ether                 123 5-Cl 2-Cl-phenyl                                                                             4-methoxy                                                                             N(CH.sub.3).sub.2                                                                            240                                                                           DCM/hexane                          124                                       187                                                                           DCM/hexane                          125 5-Cl 2-Cl-phenyl                                                                             3,4-dimethoxy                                                                         N(CH.sub.2 CH.sub.3).sub.2                                                                   213                                                                           hexane/isopropyl ether              126                                       200                                                                           hexane/isopropyl ether              127 5-Cl 2-Cl-phenyl                                                                             3,4-dimethoxy                                                                         N(CH.sub.3)CH.sub.2CH.sub.2C.sub.6 H.sub.5                                                   125-130                                                                       hexane/isopropyl ether              128                                       140-142                                                                       DCM/isopropyl ether                 129 5-Cl 2-Cl-phenyl                                                                             2,4-dimethoxy                                                                         N(CH.sub.3).sub.2                                                                            213                                 130                                       206                                 131 5-Cl 2-methoxyphenyl                                                                         3,4-dimethoxy                                                                         N(CH.sub.3).sub.2                                                                            205                                                                           hexane/isopropyl ether              132                                       206                                                                           hexane/isopropyl ether              133 5-CH.sub.3                                                                         2-Cl-phenyl                                                                             3,4-dimethoxy                                                                         N(CH.sub.2 CH.sub.3).sub.2                                                                   189                                                                           isopropyl ether                     134                                       191                                                                           isopropyl ether                     135 5-CH.sub.3                                                                         2-Cl-phenyl                                                                             2,4-dimethoxy                                                                         N(CH.sub.2 CH.sub.3).sub.2                                                                   208-209                                                                       isopropyl ether                     136                                       214-215                                                                       isopropyl ether                     137 5-Cl 2-Cl-phenyl                                                                             2,4-dimethoxy                                                                         N(CH.sub.2 CH.sub.3).sub.2                                                                   225                                 138                                       200                                 139 5-Cl 2-Cl-phenyl                                                                             4-cyano N(CH.sub.3).sub.2                                                                            242-243                                                                       THF/EtOH                            140                                       228-231                                                                       DCM/isopropyl ether                 141 5-Cl 2-Cl-phenyl                                                                             3,4-dimethoxy                                                                         N(C.sub.4 H.sub.9).sub.2                                                                     203                                 cis                                       DCM/isopropyl ether                 142 5-Cl cyclohexyl                                                                              3,4-dimethoxy                                                                         N(CH.sub.2 CH.sub.3).sub.2                                                                   117-120                             143                                       NMR                                 144 5-Cl 2-F-phenyl                                                                              4-nitro N(CH.sub.3).sub.2                                                                            230                                 cis                                                                           __________________________________________________________________________     NMR spectrum                                                                  Example 143: trans isomer                                                     0.2-1.8 ppm:m:17H:2CH.sub.3 (ethyl), 11H cyclohexyl                           2.8-3.5 ppm:m:4H:N (CH.sub.2).sub.2-                                          3.7 ppm:s:3H:OCH.sub.3 -                                                      3.75 ppm:s:3H:OCH.sub.3 -                                                     4.7 ppm:s:1H:H (indoline)                                                     5.65 ppm:s:1H:OH (indoline)                                                   6.8-7.6 ppm:m:6H:aromatic protons                                        

EXAMPLES 145 and 146

Methyl5-chloro-3-(2-chlorophenyl)-3-hydroxy-1-tosylindoline-2-carboxylate,dextrorotatory cis isomer, levorotatory cis isomer

The optical isomers of methyl5-chloro-3-(2-chlorophenyl)-3-hydroxy-1-tosylindoline-2-carboxylate,described in Example 48 of Table 1, were separated by preparativechromatography on a chiral column.

Supercritical phase analytical chromatography is first carried out onthe product of Example 48.

The column used is a Chiralcel OD® column marketed by DAICEL. Thiscolumn consists of silica gel coated with cellulose carbamate.

The eluent is a carbon dioxide/propan-2-ol/diethylamine mixture(75/25/0.3, v/v/v) used at a flow rate of 2 ml/minute. The exit pressureis 160 atmospheres, the temperature is 32° C. and UV detection iscarried out at 226 nm.

The chromatogram shows 2 peaks of equal areas and with retention timesof about 4 minutes and 5.4 minutes.

A Chiralcel® column is also used for preparative chromatography.

The sample of product to be chromatographed is dissolved in methanol (30mg/ml) and 1 ml is injected into the column. The eluent is ahexane/propan-2-ol mixture (80/20, v/v) used at a flow rate of 1.5ml/minute. UV detection is carried out at 226 nm. The analysis time is45 minutes. Twelve fractions were collected and analyzed in thesupercritical phase.

Under the same conditions, 13 injections of 30 mg are then carried out.The fractions corresponding to the first peak, collected between 16 and24 minutes, are pooled; the fractions corresponding to the second peak,collected between 29 and 42 minutes, are pooled. After passage under astream of nitrogen, each batch is recrystallized from a DCM/isopropylether/hexane mixture.

The first peak gives a product with a chromatographic purity of morethan 99.9%; this is the dextrorotatory cis isomer.

α_(D) ²⁵ =+236 (chloroform)

M.p.=174°-177° C. (after recrystallization from DCM/hexane/isopropylether)

m=130 mg

The second peak gives a product with a chromatographic purity of morethan 99.5%; this is the levorotatory cis isomer.

α_(D) ²⁵ =-238 (chloroform)

M.p.=174°-177° C. (after recrystallization from DCM/hexane/isopropylether)

m=83 mg

EXAMPLE 1a

N-methyl-N-methoxycarbonylmethyl-5-bromo-3-(2-fluorophenyl-1-(3,4-dimethoxyphenylsulfonyl )-3-hydroxy-2-indolinecarboxamide, cisisomer.

A) Methyl N-bromoacetylsarcosinate.

This compound is prepared according to T. D. Harris et al. in J.Heterocyclic Chem., 1981, 18, 423.

B) 5'Bromo-2-(3,4-dimethoxyphenylsulfonamido)-2'-fluorobenzophenone.

20 g of 2-amino-5-bromo-2'-fluorobenzophenone are heated at 85° C. for48 hours in 120 ml of dry pyridine in the presence of 20 g of3,4-dimethoxyphenylsulfonyl chloride. The mixture is cooled, poured intoice-cold water, the solid is filtered off, the solid is extracted withAcOEt, the organic phase is washed with water, a solution ofhydrochloric acid (1N), water and then saline water. After drying overmagnesium sulfate and evaporating the solvent under vacuum, a solid isobtained which is recrystallized from DCM/isopropyl ether.

m=28 g

M.p.=125°-128° C.

5-Bromo-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(N'-methyl-N'-(methoxycarbonylmethyl)carbamylmethyl)]amino-2'-fluorobenzophenone.

3.5 g of the compound prepared in Step B are dissolved in anhydrous DMFat 0° C. under argon and 250 mg of 80% sodium hydride are added; after15 minutes, 4.85 g of the compound prepared in Step B are added and themixture is left stirring at RT for 12 hours. The reaction mixture ispoured into water, the solid is filtered off and then the solid isdissolved in AcOEt, the organic phase is washed with water and then withsaline water and the solvent is evaporated under vacuum. The oilobtained is filtered on silica by eluting with a DCM/AcOEt (85/15 ; v/v)mixture. It is recrystallized from a DCM/isopropyl ether/MeOH mixture.

m=3.2 g

M.p.=136°-137° C.

D)N-methyl-N-methoxycarbonylmethyl-5-bromo-3-(2-fluorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,cis isomer.

3.2 g of product obtained in the preceding step are dissolved in DCM (3ml), 750 mg of DBU are added and the mixture is left stirring at RT for24 hours. The reaction mixture is poured onto a silica column; byeluting with DCM/AcOEt (90/10 ; v/v), a product is obtained which is themixture of the two isomers (cis and trans) of the expected compound.This product is triturated in a hexane/isopropyl ether mixture and thesolid obtained is filtered. The filtration liquors are chromatographedon an alumina column which was preequilibrated in a DCM/AcOEt (70/30 ;v/v) mixture. The least polar compound is eluted with a DCM/AcOEt (60/40; v/v) mixture and is then recrystallized from a DCM/hexane/isopropylether mixture.

M.p.=95° C. with evolution of gas.

EXAMPLES 2a and 3a

2-[(4-Benzyloxycarbonyl)-1-piperazinyl]carbonyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline,cis isomer and trans isomer.

A) 1-Bromacetyl-4-(benzyloxycarbonyl)piperazine.

A mixture of 22 g of 4-benzyloxycarbonylpiperazine and 10.1 g oftriethylamine in 200 ml of ether is cooled to 0° C. 20.2 g ofbromoacetyl bromide in 100 ml of ether are added over 30 minutes and themixture is left to return to RT. After 4 hours, the reaction mixture iswashed with water, dried, concentrated and then chromatographed onsilica. The mixture DCM/AcOEt (95/5 ; v/v) elutes the expected compoundwhich is recrystallized from DCM/isopropyl ether.

m=9 g

M.p.=100°-101° C.

B ) 2', 5-Dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenone.

5.6 g of 2-amino-2',5-dichlorobenzophenone and 5 g of3,4-dimethoxyphenylsulfonyl chloride are heated in pyridine at 100° C.overnight. The pyridine is evaporated to dryness, water is added andextraction is carried out with ethyl acetate containing a small amountof DCM. After washing more than once with water and drying over sodiumsulfate, the extract is evaporated under vacuum and 7.7 g of theexpected product are recrystallized in a DCM/AcOEt mixture.

M.p.=164° C.

C)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(4-benzyloxycarbonyl-1-piperazinylcarbonylmethyl)]aminobenzophenone.

2.3 g of the benzophenone prepared in Step B are placed in 10 ml of DMFand treated with 200 mg of 80% sodium hydride in oil. After 30 minutes,5.3 g of the compound prepared in Step A are added and the mixture isstirred for 60 hours at RT. The mixture is poured into water, theprecipitate is filtered, taken up in DCM, dried and then concentratedand chromatographed on silica. The DCM/AcOEt (90/10 ; v/v) mixtureelutes the expected product which crystallizes from a DCM/isopropylether mixture.

m=2 g

M.p.=173°-175° C.

D)2-[(4-Benzyloxycarbonyl)-1-piperazinyl]carbonyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline,cis isomer and trans isomer.

1 g of the compound obtained in the preceding step is suspended in 20 mlof methanol and 20 ml of THF and is treated with 75 mg of sodiummethylate. After 2 hours, the mixture is neutralized by the addition ofa small amount of dry ice, is concentrated to dryness and then taken upin water; the mixture is then extracted with DCM, the extract is driedand concentrated. The crude product is chromatographed on alumina, andthe DCM/AcOEt (80/20; v/v) mixture elutes the 2 isomers successively.

The least polar isomer is recrystallized from a DCM/hexane mixture. Thiscompound is the cis isomer.

m=262 mg

M.p.=169°-179° C.

The most polar isomer is recrystallized from the DCM/isopropyl ethermixture.

m=200 mg

M.p.=209°-211° C.

EXAMPLE 4a

5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-(1-piperazinylcarbonyl)indoline,cis isomer.

200 mg of the cis isomer prepared in the preceding example are dissolvedin 10 ml of ethanol and 5 ml of THF and are hydrogenolyzed at RT in thepresence of 10% Pd/C. After 30 minutes, the mixture is filtered onCelite®, the filtration liquors are concentrated and thenchromatographed on silica. The MeOH/DCM (10/90 ; v/v) mixture elutes theexpected product which is recrystallized from a DCM/isopropyl ethermixture.

m=110 mg

M.p. 230°-233° C.

EXAMPLES 5a and 6a

5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-morpholinocarbonylindoline,cis isomer and trans isomer.

A)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(morpholinocarbonylmethyl)]aminobenzophenone.

5 g of 2',5-dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenone aretreated with 350 mg of 80% sodium hydride in 30 ml of DMF at RT for 20minutes. 4.5 g of morpholinebromoacetamide are added and then themixture is stirred at RT for 48 hours. The mixture is poured into water,the precipitate is filtered, it is dissolved in DCM, the solution isdried and concentrated. The product formed is recrystallized from aDCM/isopropyl ether mixture. 5.4 g are obtained.

M.p.=173°-176° C.

B)5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-morpholinocarbonylindoline,cis isomer.

1 g of the product obtained in the preceding step is dissolved in themethanol (10 ml) and THF (20 ml) mixture and is treated with 92 mg ofsodium methylate at RT for 1 hour. The mixture is neutralized with dryice, the solvents are partly evaporated, the mixture is taken up inwater, extracted with DCM and the extract is dried, concentrated andchromatographed on alumina. The DCM/AcOEt (70/30; v/v) mixture elutesthe least polar isomer which is recrystallized from a DCM/isopropylether mixture.

m=215 mg: cis isomer

M.p.=260°-264° C.

C)5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-morpholinocarbonylindoline,trans isomer.

By the chromatography of the preceding step, a more polar product iscollected by eluting with the AcOEt/MeOH (90/10) ; v/v) mixture. Afterrecrystallizing from a DCM/isopropyl ether mixture, there is obtained:

m=513 mg: trans isomer

M.p.=240°-241° C.

EXAMPLE 7a

N-Methyl-N-carboxymethyl-5-bromo-3-(2-fluorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,cis isomer.

200 mg of the compound prepared in Example 1a are dissolved in 3 ml ofMeOH and 1 ml of water containing 13 mg of sodium hydroxide. Afterstirring for 24 hours at RT, one drop of concentrated sodium hydroxidesolution is added to bring the reaction to an end and then, after 15minutes, the mixture is acidified to pH 3 by addition of a potassiumhydrogensulfate solution. Water is added, the mixture is extracted withAcOEt and the extract is washed with water and dried over magnesiumsulfate and the solvent is evaporated under vacuum. The product obtainedis recrystallized from DCM/isopropyl ether.

M.p.=206°-208° C.

EXAMPLES 8a AND 9a

5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenyl-sulfonyl)-3-hydroxy-2-(4-ethylcarboxylatepiperidinocarbonyl)indoline,cis isomer, trans isomer.

A) Ethyl N-bromoacetyl-4-piperidinecarboxylate

This product is prepared from ethyl 4-piperidinecarboxylate, which iscommercially available.

B)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl]-N-(4-ethylcarboxylatepiperidinocarbonylmethyl)]aminobenzophenone.

8 g of 2',5-dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenone aredissolved in 100 ml of DMF and then 541 mg of sodium hydride are added.After stirring for 30 minutes, 9.5 g of the compound of Step A are addedand the mixture is left stirring for 18 hours at RT. The mixture isconcentrated under vacuum, taken up in water, extracted with ethylacetate and the extract is dried and concentrated. The oil obtained ischromatographed on silica, eluting with the AcOEt/DCM/hexane (40/10/50 ;v/v/v) mixture. The expected product crystallizes from ether.

m=3.5 g

M.p.=128° C.

C)5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-(4-ethylcarboxylatepiperidinocarbonyl)indoline,cis isomer, trans isomer.

A mixture containing 3.4 g of the compound prepared in the precedingstep and 869 mg of DBU in 10 ml of chloroform is brought to 60° C. for18 hours. The reaction mixture is then filtered on an alumina column,eluting with a DCM/AcOEt (90/10; v/v) mixture in order to obtain the cisisomer.

m=700 mg

M.p.=110° C.

Pure ethyl acetate elutes the trans isomer.

m=610 mg

M.p.=187° C.

EXAMPLES 10a and 11a

N-methyl-N-(2-pyridylethyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,cis isomer, trans isomer.

A)N-[2-(2-chlorophenylcarbonyl)-5-chlorophenyl]-N-(3,4-dimethoxyphenylsulfonyl)glycineacid.

a) 2',5-Dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenone.

This compound is prepared in Example 2a-3a, Step B.

b)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-benzyloxycarbonylmethyl]aminobenzophenone.

172 g of the product prepared previously are dissolved in 800 ml of DMFand cooled to 0° C. 11.7 g of 80% sodium hydride is added progressivelyunder nitrogen and then, after 30 minutes, 256 g of benzyl bromoacetateare added and the mixture is left stirring for 24 hours at RT. The DMFis evaporated, the residue is taken up in water, extracted with DCM, andthe extract dried and concentrated. The expected product crystallizesfrom isopropyl ether and is then recrystallized from a DCM/isopropylether mixture.

m=136.5 g

M.p.=102°-104° C.

c)N-[2-(2-Chlorophenylcarbonyl)-5-chlorophenyl]-N-(3,4-dimethoxyphenylsulfonyl)glycineacid.

50 g of the benzyl ester obtained previously are dissolved in 500 ml ofAcOEt and 2.5 g of 5% Pd/C are added under nitrogen. The solution isvigorously stirred and a stream of hydrogen is passed in for 5 hours. Atthe end of the hydrogenation, the product crystallizes. The mixture isfiltered on Celite®, the cake is washed copiously with hot DCM and thenthe organic phase is concentrated. The expected product crystallizes andis then recrystallized from the DCM/isopropyl ether mixture.

m - 33.7 g

M.p.=177°-178° C. B)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(N'-(2-(2-pyridyl)ethyl)-N'-methyl)carbamoylmethyl]aminobenzophenone.

2 g of the acid prepared in Step A are placed in 30 ml of DCM and 1.13 gof 2-(2-methylaminoethyl)pyridine, then 844 mg of triethylamine andfinally 1.92 g of BOP are added and then the mixture is left stirringfor 18 hours at RT. The mixture is taken up with water, the organicphase is separated, washed with a sodium carbonate solution, dried andconcentrated. After chromatography on silica, the expected product iscollected by eluting with the DCM/MeOH (95/5); v/v) mixture.

m=2 g

M.p.=150° C.

C)N-methyl-N-(2-pyridylethyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide.

A mixture containing 1.7 g of the product obtained in the preceding stepand 442 mg of DBU in DCM is heated at 55° C. for 18 hours. The reactionmixture is chromatographed on alumina. The AcOEt/DCM (40/60); v/v)mixture elutes the cis isomer:

m=410 mg

M.p.=191° C.

Pure AcOEt elutes the trans isomer:

m=790 mg

M.p.=154° C.

EXAMPLE 12a

2-(4-Carboxypiperidinocarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline,cis isomer.

500 mg of the cis isomer prepared in Example 9a are placed in 5 ml ofmethanol in the presence of 48 mg of sodium hydroxide in 1 ml of water.After stirring for 18 hours, the mixture is poured into water, acidifiedwith dilute hydrochloric acid, then extracted with DCM and the extractdried and concentrated. The solid obtained is purified by chromatographyon silica, eluting with the DCM/MeOH (95/5; v/v) mixture and the productobtained is then crystallized from a DCM/isopropyl ether mixture.

m=250 mg

M.p.=150° C.

EXAMPLES 13a and 14a

N-Methyl-N-(1-methyl-4-piperidyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,cis isomer and trans isomer.

A)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(N'-methyl-N'-(methyl-4-piperidyl)carbamoylmethyl]aminobenzophenone.

2 g of the acid prepared in Example 10a-11a, Step A in 50 ml of DCM aremixed with 650 mg of 4-methylamino-1-methylpiperidine in the presence of1.90 g of BOP. After stirring for 2 hours at RT, the organic phase iswashed with carbonated water, dried and concentrated. The residue isthen chromatographed on silica, eluting with the DCM/MeOH (90/10 ; v/v)mixture. 1.2 g of the expected product are obtained.

M.p.=165°-166° C.

B)N-Methyl-N-(methyl-4-piperidyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,cis isomer and trans isomer.

650 mg of the product obtained in the preceding step are treatedovernight with 100 mg of sodium methylate in 5 ml of methanol. Dry iceis added, the solvent is evaporated, the residue is taken up incarbonated water, extracted with DCM and the extract dried andconcentrated and then chromatographed on silica. The methanol/DCM (5/95; v/v) mixture elutes the 2 isomers successively. Each is thenrecrystallized from a DCM/isopropyl ether mixture.

The trans isomer is the least polar under these conditions,

m=205 mg

M.p.=181° C. Cis isomer: m=150 mg

M.p.=97° C.: contains 0.25M of isopropyl ether.

EXAMPLES 15a AND 16a

5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[4-methyl-1-piperazinylcarbonyl]indoline,cis isomer and trans isomer.

A)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((4-methyl-1-piperazinyl)carbamoylmethyl))aminobenzophenone.

This compound is obtained by the action of N-methylpiperazine on theacid prepared in Example 10a-11a Step A.

M.p.=165°-167° C.

B)5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[4-methyl-1-piperazinylcarbonyl]indoline,cis isomer and trans isomer.

The compound of the preceding step is cyclized by proceeding as inExample 12a-13a,. The 2 isomers formed are separated by chromatographyon alumina. The DCM/AcOEt (75/25; v/v) mixture elutes the least polarproduct: the cis isomer, which is recrystallized from a DCM/isopropylether mixture.

M.p.=120° C.: contains 0.25M of isopropyl ether.

The DCM/MeOH mixture elutes the most polar compound, the trans isomerwhich is then recrystallized from methanol.

M.p.=189° C.

EXAMPLES 17a and 18a

N-Isopropyl-N-methoxycarbonylethyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,cis isomer and trans isomer.

A) N-Isopropyl-N-(methoxycarbonylethyl)bromoacetamide.

90 g of isopropylamine are added dropwise to 130 g of a solution, cooledto -10° C., of methyl acrylate in 300 ml of methanol. After 72 hours atRT, the mixture is evaporated and the residue is then distilled. The oilobtained (168.3 g) is methyl 3-(N-isopropyl)-aminopropionate.

B.p.=73°-78° C. at 15 mm Hg.

29 g of the compound obtained in 100 ml DCM are mixed with 20.2 g ofbromoacetyl bromide in 100 ml of DCM at 0° C. After 12 hours at RT, thesolvent is evaporated, the residue is taken up in water, extracted withethyl acetate and the extract dried and concentrated. The oil obtainedis used as it is in the following step.

B)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(N'-isopropyl-N'-methoxycarbonylethyl)carbamoylmethyl]-aminobenzophenone.

This compound is obtained by following the usual procedure, by reactingthe product prepared in Step A with2',5-dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenone in thepresence of sodium hydride.

M.p.=135°-137° C. (recrystallization: DCM/isopropyl ether).

C)N-Isopropyl-N-methoxycarbonylethyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,cis isomer and trans isomer.

This product is obtained by cyclizing the compound prepared in Step B,in the presence of DBU. The cis isomer is separated by chromatography onalumina, eluting with a DCM/AcOEt (90/10; v/v) mixture. The product isthen crystallized from an AcOEt/hexane mixture.

M.p.=153°-155° C.

The trans isomer is obtained by eluting the alumina column with ethylacetate. The product is then recrystallized from a methanol/isopropylether mixture.

M.p.=182°-185° C.

EXAMPLES 19a and 20a

N-Methyl-N-methoxycarbonylmethyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,cis isomer and trans isomer.

The 2 isomers of this compound are prepared according to the proceduredescribed in Example 1. They are separated by chromatography on alumina.The DCM/AcOEt (80/20 ; v/v) mixture elutes the cis isomer. Thiscrystallizes from a DCM/isopropyl ether mixture in the form of a whitepowder containing 0.25 mole of isopropyl ether. It is converted to afoam by heating in vacuum.

The NMR spectrum of the cis isomer (Example 19a) is given in FIG. 1.

The trans isomer is eluted with pure AcOEt. It is recrystallized fromDCM/isopropyl ether.

M.p.=176°-178° C.

The NMR spectrum of the trans isomer (Example 20a) is given in FIG. 2.

EXAMPLES 21a AND 22a

N-Methyl-N-carboxymethyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,cis isomer and trans isomer.

These compounds are each prepared from the compounds described inExamples 19a and 20a according to the procedure described in Example 8a.

Cis isomer: M.p.=220°-222° C. after recrystallizing from a DCM/isopropylether/MeOH mixture.

Trans isomer: M.p.=222°-225° C. after recrystallizing from aDCM/isopropyl ether mixture.

EXAMPLES 23a and 24a

N-Methyl-N-carbamoylmethyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,cis isomer and trans isomer.

Each isomer is obtained from the corresponding isomer of the acidprepared in Example 21a-22a.

605 mg of the trans isomer of the acid obtained in the preceding exampleare dissolved in 10 ml of DCM, and 435 mg of BOP and 260 mg of DIPEA areadded. After 5 minutes at RT, 6 ml of 20% aqueous ammonia solution areadded with vigorous stirring and the mixture is left stirring for 4hours. A sodium carbonate solution is added and the mixture is thenextracted with DCM. The organic phase is washed successively with water,a sodium hydrogensulfate solution, and water and is then dried overmagnesium sulfate. After evaporating, the residue is chromatographed onsilica gel and is eluted with an AcOEt/MeOH (95/5; v/v) mixture. Theproduct obtained is crystallized twice from a DCM/EtOH mixture at 0° C.

M.p.=236° C.

The NMR spectrum of the trans isomer (Example 23a) is given in FIG. 3.

Using the same procedure, the cis isomer is prepared.

The expected product crystallizes from DCM/isopropyl ether. Themicronized compound, dried in vacuum at 70° C. for 8 hours, contains0.25 mole of isopropyl ether.

The NMR spectrum of the cis isomer (Example 24a) is given in FIG. 4.

EXAMPLES 25a and 26a

5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-1-(4-hydroxy-1-piperidyl)carbonylindoline,trans isomer.

This compound is prepared fromN-[2-(2-chlorophenylcarbonyl)-5-chlorophenyl]-N-(3,4-dimethoxyphenylsulfonyl)glycineacid described in Example 11a-12a, Step A.

The process is then carried out as in Example 11a-12a for the additionof 4-hydroxypiperidine, in the presence of BOP and triethylamine. Theproduct obtained is then cyclized according to the usual method in thepresence of DBU. The 2 isomers are separated by chromatography onalumina. The DCM/MeOH (99/1; v/v) mixture elutes the cis isomer.

The product crystallizes from a DCM/hexane/MeOH mixture and the solidobtained is then triturated in DCM/hexane to provide an amorphouspowder.

The cis isomer is characterized by its NMR spectrum at 388° K.

1-1.8 ppm:m:4 H:CH₂ at positions 3 and 5 of the piperidine

2.8-3.65 ppm:m:5 H:CH₂ at positions 2 and 6 of the piperidine and CH atposition 5

3.75 ppm:2s:6 H:2OCH₃

4.15 ppm:d:1H:OH on piperidine

5.45 ppm:s:1H:CH (indoline)

6.1 ppm:s:1H:OM indoline

6.8-7.6 ppm:m:10 H:M aromatic

DMSO:2.4 ppm

DOH:2.75 ppm

The DCM/MeOH (97/3; v/v) mixture elutes the trans isomer which isrecrystallized from DCM/isopropyl ether.

M.p.=232°-234° C.

SYNTHESES in the (L)-Proline series: Examples 27a, 28a, 29a and 30a.

EXAMPLES 27a and 27b

5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-(2-methoxycarbonyl)pyrrolidinocarbonyl]indoline,(cis isomerism: 2 compounds).

A) Methyl (L)-N-(bromoacetyl)prolinate.

20 g of triethylamine and 20 g of bromoacetyl bromide in 30 ml of DCMare added simultaneously to a solution of 16.7 g of methyl (L)-prolinatehydrochloride in 20 ml of DCM while maintaining the temperature at -5°C. and the mixture is then stirred at RT for 24 hours. Water is added,and the mixture is washed with a solution of KHSO₄, with water, with asodium bicarbonate solution and with water and is then dried overmagnesium sulfate. After evaporating, an oil is obtained which is driedunder vacuum. This oil, pure by TLC, is used as it is in the followingstep.

B)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((2S)-(2-methoxycarbonyl)pyrrolidinocarbonylmethyl)]-aminobenzophenone.

4.66 g of 2',5-dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenoneare dissolved in 40 ml of anhydrous DMF under argon, at 0° C., 340 mg of80% sodium hydride are added and then, after 30 minutes, 6.5 g of thecompound obtained in Step A. After 4 days at RT, the mixture is pouredinto water, extracted with AcOEt, the extract washed with water, withsaline water and then dried over magnesium sulfate and evaporated undervacuum. A solid containing a small amount of the starting brominatedderivative is eluted with a DCM/AcOEt (85/15; v/v) mixture bychromatography on silica gel. A sample is recrystallized fromDCM/isopropyl ether.

m=1.2 g

M.p.=141°-142° C.

α_(D) ²⁵ =-43.7 (c=1; MeOH/THF: 8/2; v/v)

Analysis Calculated C:54.81 H:4.44 N:4.41

Found 54.40 4.54 4.55

C)5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-(2-methoxycarbonyl)pyrrolidinocarbonyl]indoline,(cis isomerism).

1.1 g of the compound obtained in the preceding step are heated in 4 mlof methylene chloride for 24 hours with one equivalent of DBU. HPLCanalysis of an aliquot shows the existence of the expected 4 isomers.After 24 hours, the reaction mixture is poured onto an alumina column,pre-equilibrated in the DCM/AcOEt (90/10; v/v) mixture and is elutedwith the DCM/AcOEt (90/10; v/v to 70/30; v/v) mixture. 510 mg of amixture of the 2 least polar compounds are obtained in the ratio 4/1(measured by HPLC).

1°) Two successive crystallizations from DCM/isopropyl ether while coldprovide the major compound.

m=180 mg

α_(D) ²⁵ =-247 (c=0.4; chloroform)

M.p.=187°-190° C.

2°) The crystallization mother liquors of the preceding compound arechromatographed on alumina by eluting with DCM/AcOEt (85/15; v/v). Thepreceding compound is thus separated from the second, the latter isdissolved in the minimum amount of DCM and is then precipitated byaddition of the minimum amount of hexane.

α_(D) ²⁶ =+136 (c=0.24; chloroform)

EXAMPLE 28a

2-((2S)-2-Carboxypyrrolidinocarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline,cis isomer.

430 mg of the compound prepared in Example 27 are dissolved in 6 ml ofmethanol, 41 mg of sodium hydroxide in 1 ml of water are added and themixture is stirred for 24 hours at RT. The mixture is acidified to pH 3with a few drops of a potassium hydrogensulfate solution and isextracted with ethyl acetate. The extract is washed with water and isthen dried over magnesium sulfate. Chromatography is carried out on asilica column prepared in a DCM/pentane (80/20; v/v) mixture. Theunreacted ester elutes the expected acid which is then recrystallizedfrom DCM/isopropyl ether.

M.p.=232°-234° C.

α_(D) ²⁶ =-254 (c=0.3; chloroform).

EXAMPLES 29a and 29b

2-((2S)-2-Carbamoylpyrrolidinocarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline,(cis isomerism: 2 compounds).

230 mg of the compound prepared in Example 28a are dissolved in 5 ml ofDCM, 50 mg of DIPEA and then 165 mg of BOP are added and the mixture isleft for 5 minutes at RT. The mixture is cooled in an ice bath and astream of gaseous ammonia is then bubbled through for 1 minute and,after 15 minutes, for a further 1 minute. Water and then a large volumeof ethyl acetate are added in order to obtain two phases. The organicsolution is washed with a sodium carbonate solution, water, a potassiumhydrogensulfate solution, water and then saline water. After drying, theresidue is chromatographed on silica by eluting with a DCM/MeOH (93/7;v/v) mixture. The product obtained is triturated in a DCM/isopropylether/hexane mixture. It contains 1/3 mole of isopropyl ether.

α_(D) ²⁶ =-189 (c=0.23; chloroform).

The compound of Example 29a can be prepared according to anotherprocedure.

A)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((2S-2-carbamoylpyrrolidinocarbonylmethyl)]aminobenzophenone.

33.9 g of the acid prepared in Example 10a-11a, Step A are dissolved in300 ml of chloroform. 15 g of thionyl chloride are added and the mixtureis brought to reflux for 1 hour and a half. The mixture is evaporated todryness, the residue is then taken up in DCM and evaporated again. Themixture is dissolved in 300 ml of DCM, brought to 0° C. and 10.5 g of(L)-prolinamide hydrochloride are added, and then 18 g of DIPEA in 20 mlof DCM are slowly added without allowing the temperature of the reactionmixture to exceed 3° C. After one night at DCM are slowly added withoutallowing the temperature of the reaction mixture to exceed 3° C. Afterone night at RT, the reaction mixture is washed with sodium bicarbonate(2 times) and then with potassium hydrogensulfate (2 times); thereaction mixture is dried and concentrated. The crude product obtainedis dissolved in the minimum amount of DCM and added dropwise toisopropyl ether (1.2 1) with stirring. After stirring for 2 hours, theprecipitate obtained is filtered and then dried under vacuum for 6 hoursat 60° C. 42 g are collected.

α_(D) ²⁵ =-40.8 (c=1.007; chloroform).

B)2-((2S)-2-Carbamoylpyrrolidinocarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3hydroxyindoline,(cis isomerism: 2 compounds).

5 g of the product prepared in the preceding step are dissolved in 50 mlof methanol. The solution is cooled to -10° C.; 1.35 g of DBU is addedand the mixture is maintained for 60 hours at -10° C. A compoundcrystallizes; it is filtered (cis compound 1). The crystallizationliquors are neutralized with KHSO₄ and the mixture is evaporated todryness. It is taken up in water, extracted 2 times with DCM, and theextracts are dried and concentrated. The crude product obtained ischromatographed on silica by eluting with an AcOEt/DCM (28/72; v/v)mixture. A mixture is collected which is dissolved in the minimum amountof methanol while hot; the insoluble material is filtered off theliquors are then placed overnight at -4° C. and the cis compound 2crystallizes.

m=1.25 g

α_(D) ²⁵ =-196 (c=0. 351; chloroform) .

The analysis of the NMR spectrum shows the presence of one mole of MeOHper mole of product. The recrystallization of the product from ethanolmakes it possible to remove the solvent in the crystals.

M.p.=154°-162° C.

α_(D) ²⁵ =-204 (c=0 3; chloroform)

α_(D) ²⁵ =-131 (c=0.27; chloroform/methanol: 8/2: v/v)

This compound is identical, the solvent excepted, to that prepared bythe first procedure of the present example.

The compound which crystallized in Step B) above, called cis compound 1,is recrystallized from methanol.

M.p.=190° C.

α_(D) =+115 (c=0.3; chloroform)

EXAMPLE 30a

5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-2-(hydroxymethyl)pyrrolidinocarbonylindoline, cis isomerism.

A) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(2-(hydroxymethyl)pyrrolidinocarbonylmethyl)]aminobenzophenone.

This compound is obtained by reacting (L)-prolinol with the acidprepared in Example 10a-11 a, Step A, by following the usual procedure.

B ) 5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl-3-hydroxy-2-[(2S)-2-(hydroxymethyl)pyrrolidinocarbonyl]indoline, cis isomer.

1.5 g of the compound of the preceding step is cyclized in the presenceof 380 mg of DBU in 2 ml of DCM. After 3 days at RT, 1 ml of DCM isadded and the mixture is then heated at 40 ° C. overnight. The formationof 3 major compounds is observed by TLC on silica (eluent AcOEt ) .

The least polar fraction is eluted by chromatography on silica usingDCM/AcOEt (60/40 to 80/20; v/v) . A chromatography on alumina is thencarried out by eluting with DCM/MeOH (99/1; v/v) . The fraction obtainedis homogeneous by TLC. The product is recrystallized three times fromDCM/isopropyl ether. The expected product is obtained with an HPLCpurity greater than 99%.

m=155 mg

M.p.=194°-197 ° C.

α_(D) ²⁵ =-195 (c=0.2; chloroform).

SYNTHESES in the (D)-Proline series: Example 31a.

EXAMPLE 31a

5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2R)-2-(methoxycarbonyl)pyrrolidinocarbonyl]indoline,cis isomer.

A) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((2R)-2-(methoxycarbonyl)pyrrolidinocarbonylmethyl)]-aminobenzophenone.

This compound is obtained from the acid prepared in Example 10a-11a,Step A (3 g) to which are added 1.2 g of methyl (D)-prolinate and 2.8 gof BOP in 10 ml of DCM in the presence of 1.15 g of triethylamine. Themixture is left for 1 hours at RT and is then diluted with DCM, theorganic phase is washed with sodium carbonate and with potassiumhydrogensulfate, dried and concentrated. The crude product ischromatographed on silica, eluting with a DCM/AcOEt (95/5; v/v) mixture.The product obtained is then recrystallized from a DCM/isopropyl ethermixture.

M.p.=140°-141° C.

α_(D) ²⁵ =+28.5 (c=0.27; chloroform).

B)5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2R)-2-(methoxycarbonyl)pyrrolidinocarbonyl]indoline,cis isomer.

1.5 g of the preceding compound is brought to reflux overnight in 5 mlof DCM in the presence of 360 mg of DBU. The mixture is chromatographedon alumina. The mixture DCM/AcOEt (95/5; v/v) elutes the least polarfraction (m=300 mg) which is recrystallized 2 times in a DCM/isopropylether mixture.

M.p.=186°-188° C.

α_(D) ²⁵ =+245 (c=0.4; chloroform).

This compound is the enantiomer obtained from (D)-proline of thatdescribed in Example 27.

EXAMPLES 32a and 32b

N-Methyl-N-methoxycarbonylmethyl-5-chloro 3(2-chlorophenyl)-1-(4-ethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,trans isomer and cis isomer.

A) 2',5-Dichloro-2-[N-(4-ethoxyphenylsulfonyl)-N-(N'-methyl-N'-(methoxycarbonylmethyl)carbamylmethyl]aminobenzophenone.

5.7 g of 2',5-dichloro-2-(4-ethoxyphenylsulfonamido)-benzophenone aredissolved, under argon, in 40 ml of DMF and 400 mg of 80% sodium hydrideare added at 0° C.; after 15 minutes, 4.3 g of methylN-(bromoacetyl)sarcosinate are added. After 48 hours, the expectedproduct is extracted in the usual way and is then purified bychromatography on silica by eluting with DCM/AcOEt (90/10; v/v) andrecrystallizing in a DCM/isopropyl ether mixture.

M.p.=158°-160° C.

B)N-Methyl-N-methoxycarbonylmethyl-5-chloro-3-(2-chlorophenyl)-1-(4-ethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,trans isomer.

1 g of the compound obtained in the preceding step is dissolved in 4 mlof DCM and treated for 90 minutes at RT with 312 mg of TBD. A solutionof potassium hydrogensulfate is added, the DCM is evaporated undervacuum, the mixture is extracted with AcOEt and the extract is washedand dried over magnesium sulfate. The expected product is obtained bychromatography on silica gel by eluting with DCM/AcOEt (90/10; v/v).

m=590 mg

M.p.=168°-171° C. after recrystallizing from DCM/hexane.

C)N-Methyl-N-methoxycarbonylmethyl-5-chloro-3-(2-chlorophenyl)-1-(4-ethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,cis isomer.

2.96 g of the compound obtained in Step A are suspended in 20 ml ofmethanol and 10 ml of THF; 100 mg of sodium methylate are added and themixture is then left for 7 hours in the refrigerator. Water is added,the mixture neutralized with a potassium hydrogensulfate solution and apart of the methanol is evaporated under vacuum. After extracting withAcOEt, the residue is chromatographed on alumina and is then eluted witha DCM/AcOEt (80/20; v/v) mixture. 850 mg of the expected product areobtained which are recrystallized from a DCM/isopropyl ether mixture.

The NMR spectrum is given in FIG. 6.

By using methods similar to those described above, intermediatecompounds (VI)' for the synthesis of compounds (I)' according to theinvention were prepared.

The compounds (VI)' prepared are described in Table A below.

The compounds (VI)' prepared are described in Table 2A below.

                                      TABLE 1A                                    __________________________________________________________________________     ##STR29##                                                                     R".sub.1                                                                            R".sub.5                                                                             R".sub.2                                                                          ##STR30##       M.p. (°C.) or IR Solvent             __________________________________________________________________________    Br    3,4-CH.sub.3 O                                                                       F                                                                                  ##STR31##      82-83 DCM/isopropyl ether                    Cl    3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR32##      164-166 DCM/isopropyl ether                  Cl    3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR33##      128 DCM/isopropyl ether                      Cl    3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR34##      105 DCM/isopropyl ether                      Cl    2,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR35##      142-143 MeOH                                 CH.sub.3 O                                                                          3,4-CH.sub.3                                                                         Cl                                                                                 ##STR36##      IR (1)                                       Cl    3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR37##      85 Isopropyl ether/DCM                       Br    3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR38##      IR (2)                                       Cl    3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR39##      199 DCM/isopropyl ether                      Cl    3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR40##      135  Isopropyl ether/ DCM/AcOH               Cl    3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR41##      113 DCM/isopropyl ether                      Cl    3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR42##      160 isopropyl ether                          Cl    3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR43##      197-198                                      Cl    3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR44##      (3)                                          __________________________________________________________________________     IR (1) (DCM) 1740 cm.sup.-1  fine                                              1680 cm.sup.-1  broad                                                        IR (2) (DCM) 1735 cm.sup.-1  fine                                              1660-1680 cm.sup.-1  split                                              

(3) This compound is characterized by its optical rotation:

α_(D) ²⁵ =-36.8 (c=0.44; chloroform). ##STR45##

For each compound of formula (I)' which has the substituents R'₁, R"₅,R"₂ and NR'₆ R'₇ of the table below, the cis isomerism is shown and thenthe trans isomerism, except when otherwise indicated.

    __________________________________________________________________________     Example                                                                             R'.sub.1                                                                          R'.sub.5                                                                             R'.sub.2                                                                          ##STR46##       M.p. (°C.) or                    __________________________________________________________________________                                         NMR Solvent                              33a 34a                                                                             Br  3,4-CH.sub.3 O                                                                       F                                                                                  ##STR47##      87-95 NMR                                35a 36a                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR48##      100-103 154-157 DCM/isopropyl ether      37a cis                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR49##      140-144 DCM/isopropyl ether              38a mixture                                                                         Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR50##      222-225 DCM/isopropyl ether              39a  40a                                                                            Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR51##      NMR NMR                                  41a cis                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR52##      166 DCM/isopropyl ether                  42a 43a                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR53##      119 AcOEt/isopropyl ether 228 MeOH       44a cis                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR54##      179 DCM/isopropyl ether                  45a 46a                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR55##      109 DCM/isopropyl ether 196 DCM/isopr                                         opyl ether                               47a 48a                                                                             Cl  2,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR56##      134 (iPr).sub.2 O 195 DCM/isopropyl                                           ether                                    49a cis                                                                             Cl  3,4-CH.sub.2 O                                                                       Cl                                                                                 ##STR57##      236 isopropyl ether                      50a 51a                                                                             CH.sub.3                                                                          3,4-CH.sub.3                                                                         Cl                                                                                 ##STR58##      154 isopropyl ether 87 isopropyl                                              ether                                    52a   Cl  2,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR59##      194 MeOH/isopropyl ether                 53a cis                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR60##      195 isopropyl ether/DCM                  54a 55a                                                                             Br  2,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR61##      138-140 isopropyl ether 140 isopropyl                                          ether                                   56a 57a                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR62##      242-245 DCM/isopropyl ether 225                                               MeOH/isopropyl ether                     58a 58b                                                                             Cl  2,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR63##      228 MeOH/isopropyl ether 221                                                  DCM/MeOH                                 59a 59b                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR64##      131-134 DCM/isopropyl ether/hexane                                            121 DCM/ether/hexane                     60a 61a                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR65##      162-166 DCM/isopropyl ether 130                                               DCM/isopropyl ether/hexane               62a 63a                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR66##      176 isopropyl ether/DCM NMR              64a 65a                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR67##      148  isopropyl ether/DCM 122                                                  isopropyl ether/DCM                      66a 67a                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR68##      NMR 168 isopropyl ether                  68a cis                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR69##      179-182 DCM/isopropyl ether              69a cis                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR70##      139 DCM/isopropyl ether                  70a cis                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR71##      130 isopropyl ether                      71a cis                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR72##      136 DCM/isopropyl ether                  72a cis                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR73##      135 DCM/isopropyl ether                  73a 74a                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR74##      197 MeOH/isopropyl ether 211 MeOH        75a cis                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR75##      NMR                                      76a cis                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR76##      Fumarate 152-156 DCM/isopropyl                                                ether                                    76b 76c                                                                             Cl  3,4-CH.sub.3 O                                                                       Cl                                                                                 ##STR77##      137 isopropyl ether/MeOH/hexane                                               183-185 hexane                           __________________________________________________________________________

EXAMPLE 34a

analysis: calculated C: 55.54-4.24N:3.93 found 55.72 4.57 3.83

NMR spectra at 200 MHz (DMSO: 2.5 ppm) Example 34a: FIG. 5 Example 38a

0.7-1.1 ppm: m:6 H:2CH₃ (Et)

2-4 ppm:m: 17 H:2CH₂ (Et) , 2CH₂ --N, N--CH₃, 2OCH₃

5.2-5.7 ppm:3s:1 H:H (indoline)

6.2-8.2 ppm:m: 11 H:OH+aromatics

Example 39a

0.3-1.2 ppm:m:3 H:CH₂ (Et)

1.5-4.3 ppm:m: 15 H:CH₂ --CO, CH₂ (Et) , CH₂ --N, 2OCH₃, CO₂ CH₃

52-5.6 ppm:3s:1 H:H (indoline)

6.2-8.2 ppm:m:11 H:OH+aromatics

Example 40a

0.8-1.1 ppm:m:3 H:CH₃ (Et)

2.2-3.9 ppm:m:15 H:CH₂ CO, CH₂ (Et), CH₂ N, CO₂ CH₃, 2OCH₃

5.3-5.7 ppm:2s:1 H:H (indoline)

6.6-8.2 ppm:m:11 H:OH+aromatics

Example 63a

0.4-1 ppm: split t:3 H:CH₂ --CH₂ --CH₃

5 ppm:m:2 H:CH₂ --CH₂ --CH₃

2.5-4.4 ppm:m: 13 H:CH₂ --CH₂ --CH₃, NCH₂ COOCH₃, 2OCH₃

5.2-5.8 ppm; bs :1 H:H (indoline)

6.5-8.3 ppm:m: 11 H:OH+aromatics

Example 66a

0 to 1.5 ppm:m:3 H:CH₂ --CH₃

2.3-5.8 ppm:m: 14 H:CH₂ --CH₃, NCH₂ COOCH₃, 2OCH₃, H (indoline)

6.1-8.3 ppm:m:11 H:OH+aromatics

Example 75a

1.95 ppm:bs:2 H:NH₂

2.7 to 5.3 ppm:m:12 H:2OCH₃, 2NCH₂, H(indoline), CHNH₂

6 to 8.3 ppm:m: 11 H:OH+aromatics

Example 76b

α_(D) ²⁵ =+102 (c=0.35; chloroform)

Example 76c

α_(D) ²⁵ =-158 (c=0.2; chloroform).

Some compounds according to the invention described in Table 2 areuseful in the preparation of other compounds according to the invention.For example, compound 41a was obtained from compound 39a by treatment inbasic medium in methanol MeOH/H₂ O. Compound 49a was prepared fromcompound 41a by treatment with aqueous ammonia in the presence of DIPEAand BOP.

EXAMPLE 77a

N-Ethyl-N-(2-aminoethyl )-5-chloro-3-(2-chlorophenyl)-1-3,4-dimethoxyphenylsulfonyl )-3-hydroxy-2-indolinecarboxamide, (cisisomerism).

500 mg of compound 49a are dissolved in 10 ml of acetonitrile and 10 mlof water and 252 mg of pyridine and 380 mg ofbis(trifluoroacetoxy)iodobenzene are added. After stirring for 2 hours,the mixture is taken up in a solution of hydrochloric acid, extractedwith ether, alkalized with dilute sodium hydroxide solution, extractedwith DCM and the extract is dried and concentrated. An oil is obtainedand the expected product then crystallizes from ether.

m=150 mg

M.p.=164° C.

EXAMPLE 78a

N-Ethyl-N-[(1S)-1-(ethoxycarbonyl)ethyl]-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,(cis isomerism).

A)N-[2-(2-Chlorophenylcarbonyl)-5-chlorophenyl]-N-(3,4dimethoxyphenylsulfonyl)glycineacid chloride.

A mixture containing 11 g of the acid prepared in Example 10a-11a, StepA) and 5 g of thionyl chloride in 10 ml of chloroform is heated for 1hour at 60° C. The mixture is left to return to RT, concentrated undervacuum and the residue taken up in DCM (2 times). A yellow oil isobtained which is used as it is in the following step.

IR: 1800 cm⁻¹ (C=O)

B)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(N'-ethyl-N'-((1S)-1-(ethoxycarbonylethyl)ethoxycarbamoylmethyl)]aminobenzophenone.

The preparation of this compound was carried out according to J. Org.Chem., 1985, 50, 945-950.

5.15 g of (L)-Boc(N-Et)AlaOEt is treated with 10 ml of TFA at 0° C. inorder to remove the Boc group. The mixture is concentrated under vacuum,taken up in 20 ml of DCM, cooled to -78° C. and 2 equivalents of TEA andthe acid chloride prepared in the preceding step, dissolved in DCM, areadded. After 18 hours at RT, the mixture is extracted with DCM, theextract is washed with water and then chromatographed on silica byeluting with a DCM/AcOEt (90/10; v/v) mixture. The expected productcrystallizes from isopropyl ether.

M.p.=112° C.

m=8 g

C)N-Ethyl-N-[(1S)-1-(ethoxycarbonyl)ethyl]-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,(cis isomerism).

The compound obtained in the preceding step is stirred at RT for 18hours in 10 ml of THF and 20 ml of ethanol, in the presence of 1.46 g ofDBU. The mixture is concentrated under vacuum, the residue is taken upin DCM, washed with water, concentrated and the product chromatographedon alumina by eluting with AcOEt/DCM (10/90; v/v).

0-0.9 ppm: split d:3 H:CH--CH₃

0.9-1.7 ppm:m:6 H:2CH₃ (ethyl)

2.6 to 5.8 ppm:m:12 H:2OCH₃, NCH₂, OCH₂, NCH, COCH

6.1 to 8.3 ppm:m:11 H:OH--10 H aromatics

EXAMPLES 79a and 80a

N,N-Di[2-(methoxycarbonyl)ethyl]-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,cis isomer and trans isomer.

A) N,N-Di[2-(methoxycarbonyl)ethyl]benzylamine.

Preparation according to J. Am. Chem. Soc., 1950, 72, 3298.

107 g of benzylanine in 200 ml of ethanol are cooled in an ice bath and172.2 g of methyl acrylate in 250 ml of ethanol are slowly added. After13 days at RT, the solvent is evaporated under vacuum and a part of theoily residue is then distilled.

B.p.=135°-140° C. at 0.6 mm Hg

m=30 g

IR: 1730 cm⁻¹

B) N,N-Di[2-(methoxycarbonyl)ethyl]amine.

27.9 g of the amine obtained in the preceding step, placed in 500 ml ofmethanol, are mixed with 3 g of 5% palladium on charcoal and are treatedunder hydrogen pressure for 1 hour. The mixture is filtered on Celite®,rinsed with methanol and the solvent evaporated under vacuum; theresidual oil is used as it is in the following step.

C) N,N-Di[2-(methoxycarbonyl)ethyl]bromoacetamide.

A mixture containing 14.3 g of the amine prepared in the preceding step,100 ml of DCM and 10.6 ml of TEA is cooled in an ice bath; 15.3 g ofbromoacetyl bromide are added dropwise and the mixture is then leftstirring for 48 hours at RT. The mixture is extracted with DCM, theextract is washed with water and then a chromatography is carried out onsilica by eluting with a DCM/MeOH (97/3 ; v/v) mixture. The expectedproduct is obtained in the form of an oil.

m=15.9 g

IR: 1650 cm⁻¹ and 1730 cm⁻¹.

D)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-[N',N'-di(2-(methoxycarbonyl)ethyl)carbamoylmethyl]]-aminobenzo-phenone.

14.3 g of 2',5-dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenoneare placed in 180 ml of DMF and 1.1 g of sodium hydride are added inportions. After stirring for 1 hour at RT, the mixture is cooled in anice bath and 14.3 g of the product prepared in the preceding step areadded and the mixture is left stirring for 72 hours at RT. The mixtureis extracted with DCM, the extract is washed with water and thenchromatographed on silica by eluting with a DCM/AcOEt (93/7; v/v)mixture.

m=28.4 g

M.p.=130° C.

E)N,N-Di[2-(methoxycarbonyl)ethyl]-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,cis isomer.

12 g of the compound prepared in the preceding step and 0.930 g ofsodium methylate in 150 ml of methanol are mixed at 0° C. and themixture is then left stirring overnight at RT. The reaction mixture isneutralized by addition of 5% KHSO₄ and the solvent is then evaporatedunder vacuum. The residue is chromatographed on alumina by eluting witha DCM/AcOEt (8/2; v/v) mixture. 2.4 g of the expected product arerecovered which are crystallized from methanol.

M.p.=175° C.

F)N,N-Di[2-(methoxycarbonyl)ethyl]-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,trans isomer.

The chromatography of the preceding step is continued and elution iscarried out with a DCM/MeOH (9.5/0.5; v/v) mixture. 1.82 g of the transisomer is obtained which crystallizes from isopropyl ether.

M.p.=85° C.

EXAMPLES 81a, 82a and 83a

2-((2R)-2-Carbamoylthiazolidinocarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline,(cis isomerism: 2 compounds and trans isomerism).

A) (L)-4-Thiazolidinecarboxamide.

This compound is prepared according to J. Med. Chem., 1981, 2.4, 692.

B) 2', 5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((2R)-2-carbamoylthiazolidinocarbonylmethyl)]-aminobenzophenone.

This compound is obtained by the usual methods from the acid prepared inExample 10a-11a, Step A).

M.p.=125° C. after crystallizing from ether.

C) 2-((2R)-2-Carbamoylthiazolidinocarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl )-3-hydroxyindoline.

4.3 g of the product obtained in Step B) are cyclized in 90 ml of MeOHat RT in the presence of 1 g of DBU. The mixture is concentrated, theresidue is taken up in water and DCM, the layers are separated, theorganic layer is washed with KHSO₄ and then dried and concentrated. Theresidue is chromatographed on alumina by eluting with DCM/MeOH (97/3;v/v). The compound is obtained in the cis form (mixture of 2diastereoisomers): 1.5 g, and then in the trans form (mixture of 2diastereoisomers): m=1 g.

a) The cis fraction is crystallized from MeOH/DCM in order to obtain ciscompound 1.

M.p.=176° C. after crystallizing from isopropyl ether.

α_(D) =+57 (c=0.1; chloroform).

b) The crystallization liquors of the preceding product arechromatographed on silica by eluting with AcOEt/DCM (30/70; v/v). Thecis compound 2 obtained is recrystallized from ether.

M.p.=205° C.

e_(D) =-185 (c=0.3; chloroform).

c) The trans fraction (mixture of 2 diastereoisomers) is recrystallizedfrom isopropyl ether.

M.p.=170° C.

EXAMPLES 84a, 85a, 86a and 86b

5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-2-(N,N-dimethylthiocarbamoyl)pyrrolidinocarbonyl]indoline,cis isomerism (2 compounds), (trans isomerism: 2 compounds).

A) (L) (N'-Boc )-N,N-Dimethylprolinethioamide

This compound is prepared according to J. Med. Chem., 1989, 2178.

2.36 g of (N'-Boc)-N,N-dimethylprolinamide are heated in anhydroustoluene under argon at 80° C. for 4 hours in the presence of 2.3 g ofLawesson's reagent. After 24 hours, the solvent is evaporated andisopropanol is added. The precipitate formed is separated, theisopropanol is evaporated and the residue is chromatographed on silicaby eluting with hexane/AcOEt (30/70; v/v). The product obtained isrecrystallized while cold from DCM/isopropyl ether (30/70 ; v/v).

M.p.=62° C.

B)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((2S)-2-(N',N'-dimethylthiocarbamoyl)pyrrolidinocarbonylmethyl)]aminobenzophenone.

3 g of the product prepared in the preceding step are dissolved in 10 mlof DCM and treated at 0° C. for 2 hours with 10 ml of TFA. The mixtureis evaporated to dryness, then 20 ml of DCM and 6.1 g of the acidprepared in Example 10-11, Step A) are added at 0° C. and the mixture isneutralized with 3 g of DIPEA. 5.15 g of BOP are dissolved in 30 ml ofDCM and this solution is added to the preceding solution at 0° C. over30 minutes; the pH is maintained at neutral by the addition of DIPEA andthe mixture is left stirring for 3 hours at 0° C. After one night at RT,the mixture is extracted in the usual way and then chromatographed onsilica by eluting with DCM/AcOEt (85/15; v/v). The product obtained isrecrystallized from isopropyl ether.

M.p.=182°-185° C.

α_(D) =-72° (c=0.32; chloroform).

C)5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-2-(N,N-dimethylthiocarbamoyl)pyrrolidinocarbonyl]indoline(cis isomerism: 2 compounds, and trans isomerism: 2 compounds).

3.8 g of the compound obtained in the preceding step are dissolved in 15ml of DCM and the mixture is heated at reflux for 36 hours in thepresence of 850 mg of DBU. The different isomers formed are separated bysuccessive chromatographic runs on silica.

a) Using DCM/AcOEt (85/15; v/v), the expected compound is eluted firstin the form of a mixture of 2 cis diastereoisomers. The least solublediastereoisomer is crystallized 2 times from a DCM/isopropylether/methanol mixture and is then recrystallized from the minimumamount of DMF at 60° C. followed by addition of 2 volumes of ethanol.

M.p.=270° C.

α_(D) =-278 (C=1; chloroform).

b) The crystallization liquors of the preceding mixture are taken up inand the second cis diastereoisomer crystallizes from a DCM/isopropylether mixture.

M.p.=249°-251° C.

α_(D) =+42 (c=0.22; chloroform).

c) The chromatography fractions eluted last, as well as thecrystallization mother liquors of fractions a) and b), are combined, andare chromatographed again on silica by eluting with hexane/AcOEt (20/80;v/v). Isolated first is a fraction which is recrystallized 3 times froma DCM/isopropyl ether mixture and an insoluble material is removed on apaper between each recrystallization. The trans isomer 1 is thusobtained.

M.p.=191-193

α_(D) =+74.5 (c=0.2; chloroform).

d) The second fraction contains trans isomer 2 which is recrystallizedfrom a DCM/isopropyl ether mixture and crystallizes with 1/3 mole ofisopropyl ether.

M.p.=170° C.

α_(D) =-266 (C=0.14; chloroform).

EXAMPLES 87a, 88a and 89a

2-((2S)-2-Carbamoylpyrrolidinocarbonyl)-5-chloro-3-cyclohexyl-1-(3,4-dimethoxyphenylsulfonyl )-3-hydroxyindoline, (cis isomerism: 2 compounds, trans isomerism).

A) 5-Chloro-2-[N-(3,4-dimethoxyphenylsulfonyl)amino]cyclohexylphenone.

A solution of 35.6 g of 2-amino-5-chlorocyclohexylphenone and 39.5 g of3,4-dimethoxyphenylsulfonyl chloride in 340 ml of pyridine is leftstirring for 24 hours at RT. The solvent is evaporated under vacuum andthe residue is then washed with water and with an acid solution (0.5NHCl). The expected product crystallizes from ethanol.

M.p.=135 ° C.

m=56.1 g.

B) 2- [(N-Benzyloxycarbonylmethyl-N-(3,4-dimethoxyphenylsulfonyl))amino]-5 -chlorocyclohexylphenone.

3.2 g of sodium hydride are added in portions to 52.6 g of the compoundprepared in the preceding step in 520 ml of DMF and the mixture is leftstirring for 1 hour at RT. After cooling in the ice bath, 21 ml ofbenzyloxycarbonylmethyl bromide are added dropwise and the mixture isleft stirring for 24 hours at RT. The solvent is evaporated under vacuumand the residue is taken up in water. It is extracted with DCM and theextract is washed with water; the product obtained is used as it is inthe following step.

C)N-(5-Chloro-2-(cyclohexylcarbonyl)phenyl)-N-(3,4-dimethoxyphenylsulfonyl)glycine.

The compound obtained in the preceding step is placed with 3.9 g of 5%palladium on charcoal in 700 ml of acetic acid under hydrogen (1atmosphere). At the end of the reaction, the palladium is filtered onCelite® and rinsed with hot acetic acid; the solvent is evaporated undervacuum and the residue is taken up in water. It is extracted with DCMand the extract is washed with water and then with a concentrated NaHCO₃solution. The residue obtained is chromatographed on silica by elutingwith a DCM/MeOH (97/3; v/v) mixture. The expected product crystallizesfrom ethanol.

M.p.=160° C.

m=22.4 g.

D) 5-Chloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((2S)-2-carbamoylpyrrolidinocarbonylmethyl)]-aminocyclohexylphenone.

A mixture containing 9.92 g of the acid prepared in the preceding step,3 g of (L)-prolinamide hydrochloride and 3.5 ml of DIPEA in 75 ml of DCMis cooled to 0° C. 8.84 g of BOP in solution in DCM are added and the pHis maintained at 7 by addition of DIPEA. The mixture is left stirringfor 24 hours at RT. The mixture is extracted with DCM, and the extractwashed with a saturated NaHCO₃ solution, a saline solution, a 5% KHSO₄solution and again with a saline solution. The product ischromatographed on silica by eluting with a DCM/MeOH (96/4; v/v)mixture. The expected product solidifies in isopropyl ether.

M.p.=110° C.

m=7.3 g

α_(D) =-53.9 (c=1; chloroform)

E)2-((2S)-2-Carbamoylpyrrolidinocarbonyl)-5-chloro-3cyclohexyl-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline,cis isomerism (2 compounds), trans isomerism.

5.9 g of the compound prepared in the preceding step and 1.67 g of DBUare placed in 60 ml of methanol with stirring at 0° C. for 48 hours. Thesolvent is evaporated under vacuum, water is added, the mixture isextracted with DCM and the extract is then washed with a 5% KHSO₄solution. The product is chromatographed on alumina by eluting withDCM/MeOH (98/2; v/v).

a) The least polar fraction contains the 2 cis isomers. This fraction isrecrystallized from methanol. The first compound thus obtained (cis 1)is pure by HPLC.

M.p.=185° C.

By recrystallization of the mother liquors from MeOH, a second compoundis obtained (cis 2). HPLC purity: 75% (it contains 25% cis 1).

M.p.=132° C.

b) The most polar fraction contains the trans isomer in the form of anapparently single compound which is obtained by recrystallizing frommethanol.

M.p.=240° C.

α_(D) =-55.1 (c=1; chloroform).

EXAMPLE 89b

2-((2S)-2-Carbamoylpyrrolidinocarbonyl)-5-chloro-3-cyclohexyl-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline,cis isomerism (2 compounds), trans isomerism.

By using a procedure similar to that described for Examples 87a, 88a and89a, an analogous compound in the (D)-proline series is prepared.

The compound obtained after crystallizing from a DCM/MeOH mixture hasthe trans configuration.

M.p.=238° C.

α_(D) =+164 (c=0.245; chloroform/methanol, 8.2, v/v).

The NMR spectrum of this compound and of that described in Step E b) ofthe preceding example are identical.

EXAMPLE 90a

5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-2-[(2S)-2-(N-methylaminocarbonyl)pyrrolidinocarbonyl]-3-hydroxyindoline,cis isomer.

920 mg of the compound prepared in Example 28a are placed, withstirring, in 20 ml of DCM containing 371 mg of BOP for 15 minutes, astream of monomethylamine is bubbled through for 10 minutes and thestirring is maintained for an additional 30 minutes. The mixture istaken up in water, the layers separated, the organic layer washed withpotassium hydrogensulfate and with sodium carbonate, dried andconcentrated. The residue is chromatographed on silica by eluting withDCM/methanol (97.5/2.5; v/v). The expected product is collected whichcrystallizes from an isopropyl ether/DCM mixture.

m=750 mg

M.p.=158° C.

α_(D) =-216 (c=0.3; chloroform).

By operating as in the previously described examples (Examples 27a to31a and 90a) and by using derivatives of (L)-proline (except whenotherwise indicated), other intermediate compounds (VI)' for thesynthesis of the compounds (I)' according to the invention wereprepared.

The compounds (VI)' prepared are described in Table A below.

The Compounds (I)' prepared are described in Table 4A below.

                                      TABLE 3A                                    __________________________________________________________________________     ##STR78##                                                                     R".sub.5                                                                             ##STR79##      M.p.(°C.)                                                                           α.sub.D.sup.25  (chloroform)        __________________________________________________________________________    3,4-CH.sub.3 O                                                                        ##STR80##                  +45 c = 1.015                              3,4-CH.sub.3 O                                                                        ##STR81##     161-163 DCM/isopropyl ether                                                                -70.8 c = 0.48                             2,4-CH.sub.3 O                                                                        ##STR82##     145-148      -17.5 c =  3.36                            3,4-CH.sub.3 O                                                                        ##STR83##     ≃110 DCM/isopropyl ether                  3,4-CH.sub.3 O                                                                        ##STR84##     148 isopropyl ether/MeOH                                __________________________________________________________________________

                                      TABLE 4A                                    __________________________________________________________________________     ##STR85##                                                                     Example                                                                              R'.sub.1                                                                           R".sub.5                                                                             ##STR86##      M.p.(°C.)                                                                          α.sub.D.sup.25                                                         (chloroform)                    __________________________________________________________________________    91a cis 1                                                                            Cl   3,4-CH.sub.3 O                                                                        ##STR87##     115 MeOH    +188 c = 0.33                   92a cis 2                                                                            Cl                         204         -114*                                                             MeOH/DMF    c = 0.31                        93a cis                                                                              Cl   3,4-CH.sub.3 O                                                                        ##STR88##     198-201 DCM/isopropyl ether                 94a cis                                                                              Cl   2,4-CH.sub.3 O                                                                        ##STR89##     205-207 DCM/isopropyl ether                 95a cis                                                                              Cl   2,4-CH.sub.3 O                                                                        ##STR90##     221 DCM/isopropyl ether                                                                   -242 c = 0.254                  96a cis                                                                              Cl   3,4-CH.sub.3 O                                                                        ##STR91##                 -234 c = 0.32                   97a cis                                                                              Cl   3,4-CH.sub.3 O                                                                        ##STR92##                 -214 c = 0.32                   98a cis 1                                                                            Cl   3,4-CH.sub.3 O                                                                        ##STR93##     105-115 DCM/isopropyl                                                                     +174.6 c = 0.3                  99a cis 2                         175         -214.6                                                            DCM/isopropyl ether                                                                       c = 0.3                         100a trans 1                                  -155                                                                          c = 0.2                         101a trans 2                      177         +95.2                                                             DCM/isopropyl ether                                                                       c = 0.2                         102a cis 1                                                                           Cl   3,4-CH.sub.3 O                                                                        ##STR94##     135 isopropyl ether                                                                       -162                            103a cis 1                                                                           Cl   3,4-CH.sub.3 O                                                                        ##STR95##     145 DCM/isopropyl ether                                                                   -167 c = 0.4                    103b cis 1 cis 2                                                                     Cl   3,4-CH.sub.3 O                                                                        ##STR96##                                                 104a cis 1                                                                           Cl   3,4-CH.sub.3 O                                                                        ##STR97##     210 ether   -177.5  c = 0.2                 104b cis 1 cis 2                                                                     Cl   3,4-CH.sub.3 O                                                                        ##STR98##                                                 105a   CH.sub.3 O                                                                         3,4-CH.sub.3 O                                                                        ##STR99##     200 EtOH    -195 c = 0.2                    106a                              215         +127                                                              MeOH        c = 0.2                         107a   CH.sub.3 O                                                                         3,4-CH.sub.3 O                                                                        ##STR100##    198         -63.3 c = 0.117 (CHCl.sub.3                                                   /MeOH 8/2;v/v)                  108a   Cl   2,4-CH.sub.3 O                                                                        ##STR101##    274 DCM/MeOH                                                                              -225 c = 0.372 (CHCl.sub.3                                                    /MeOH 8/2;v/v)                  108b cis                                                                             Cl   3,4-CH.sub.3 O                                                                        ##STR102##                -198.7 c = 0.24                 __________________________________________________________________________     *Example 92a: Other measured optical rotation:                                α.sub.D.sup.25 = -39.5 (c = 0.17; CHCl.sub.3 /MeOH: 8/2:v/v).      

The compound of Example 107a is the enantiomer of that of Example 106a.

The compound of Example 108b was prepared from the compound of Example28a by reacting with hydroxylamine hydrochloride in DMF and byactivating with the reagent BOP in the presence of DIPEA.

Some compounds according to the invention, described in Table 4A above,are useful for the preparation of other compounds. Thus, the compound ofExample 99a makes it possible to obtain the compound of Example 10 b,then that of Example 103a and finally that of Example 104a.

EXAMPLE 109a2-((2S,4S)-4-Azido-2-(methoxycarbonyl)pyrrolidinocarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline,cis isomer.

A)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((2S,4R)-4-hydroxy-2-(methoxycarbonyl)pyrrolidinocarbonylmethyl)]amino-benzophenone.

15 g of the acid prepared in Example 10a-11a, Step A) and 6.25 g ofmethyl (2S,4R)-4-hydroxyprolinate hydrochloride are heated to 0° C. in150 ml of DCM in the presence of 7.4 g of DIPEA. A solution of 12.7 g ofBOP in 30 ml of DCM is added dropwise over 30 minutes and the amount ofDIPEA necessary to neutralize the solution is added. After one night atRT, the mixture is extracted in the usual way and chromatographed onsilica by elution with a DCM/AcOEt (60/40; v/v) mixture. The expectedproduct crystallizes from a DCM/ether/isopropyl ether mixture.

M.p.=128°-131 ° C.

α_(D) =+8.5 (c=0.38; chloroform).

B)2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((2S,4R)-4-mesyloxy-2-(methoxycarbonyl)pyrrolidinocarbonylmethyl)]aminobenzophenone.

2 g of the compound obtained in the preceding step are dissolved at 0°C. in 10 ml of DCM. 550 mg of triethylamine and then 550 mg ofmethanesulfonyl chloride are added and the mixture is left at 0° C. for20 hours. Water is added and the organic layer is washed with 0.5Nhydrochloric water, with water and then with a sodium bicarbonatesolution, dried over magnesium sulfate and evaporated. The oil obtainedis used as it is in the following step.

C)2-[N-((2S,4S)-4-azido-2-(methoxycarbonyl)pyrrolidinocarbonylmethyl)-N-(3,4-dimethoxyphenylsulfonyl)]amino-2',5-dichlorobenzophenone.

11 g of the product prepared in the preceding step are heated in 60 mlof DMSO at 80°-90° C. in the presence of 2.7 g of sodium azide for 18hours. The mixture is poured into water, extracted with ethyl acetate,the organic layer washed with water, dried and chromatographed on silicaby eluting with a pentane/AcOEt (50/50; v/v) mixture. An oil (10 g) isobtained.

α_(D) =-25.5 (c=0.39; chloroform, T=26° C.).

D)2-((2S,4S)-4-Azido-2-(methoxycarbonyl)pyrrolidinocarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline,cis isomer.

3.38 g of the product obtained in the preceding step are cyclized underthe usual conditions in the presence of DBU. The expected product isobtained which is recrystallized from DCM/isopropyl ether.

m=755 mg

M.p. 200°-202° C.

α_(D) =-176 (c=0.21; chloroform, T=26° C).

EXAMPLE 110a

2-[(2S,4S)-4-(N-Benzyloxycarbonyl-N-methyl)amino-2-(methoxycarbonyl)pyrrolidinocarbonyl]-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline,cis isomer.

A) Methyl ester of (N-Boc)-4-hydroxyproline.

The starting material is the hydrochloride of the methyl ester of(2S,4R)-4-hydroxyproline.

19 g of this compound are suspended in 100 ml of THF, 22.9 g of (Boc)₂ Oare added and then the mixture is cooled to 0° C. 21.2 g oftriethylamine in 25 ml of THF are added dropwise and then the mixture isstirred for 12 hours at 0° C. and 4 hours at 60° C. Water is added, themixture is extracted with ethyl acetate, the organic layer is washedwith water, with a potassium hydrogensulfate solution (4 times), withwater and then with saline water. The solvent is evaporated and an oil(21.6 g) is isolated which contains a small amount of (BOC)₂ O.

B) Methyl ester of (2S,4R)-(N-Boc)-4-mesyloxyproline.

A solution of 22.9 g of the product prepared in the preceding step in250 ml of DCM is cooled to 0° C. 22.9 g of mesyl chloride in 10 ml ofDCM are added dropwise, then 9.4 g of triethylamine in 100 ml of DCM areadded dropwise and the mixture is left to return to RT overnight. Themixture is evaporated to dryness, water is added, the mixture isextracted with AcOEt, the organic layer is washed with water and salinewater and dried over magnesium sulfate. After a second evaporation, anoil is obtained which is used as it is in the following step.

C) Methyl ester of (2S,4S)-(N-Boc)-4-azidoproline.

This compound is prepared from that obtained in Step B. 15.2 g of themethyl ester of (N-Boc)-4-mesyloxy-2-hydroxyproline are dissolved in 70ml of DMSO and the solution is heated at 90° C. for 5 hours in thepresence of 3.05 g of sodium azide. The mixture is cooled, water isadded, the mixture is extracted with AcOEt, the organic layer is washedwith water and saline water and dried over MgSO₄. The oil obtained ispurified by chromatography on silica by eluting with the AcOEt/hexane(40/60; v/v) mixture.

α_(D) =-37.8 (C=3; chloroform)

lit. α_(D) =-36.6 (c=2.8; chloroform) D. J. Abrahamer al., J. Med.Chem., 1983, 549, 26.

D) Methyl ester of (2S,4S)-(N-Boc)-4-aminoproline.

8.45 g of the compound obtained in Step A are dissolved in 100 ml ofmethanol, 500 mg of 10% Pd/C are added and the mixture is hydrogenatedat 4 0 ° C. for 18 hours. The catalyst is filtered off, half themethanol is evaporated, 100 ml of 0.5N HCl are added, the remainder ofthe methanol is then evaporated and the unreacted starting material isextracted with AcOEt. The aqueous phase is treated with sodium carbonateand the fraction containing the expected product (m=4.35 g) is extractedwith AcOEt.

E) Methyl ester of (2S,4S)-(N-Boc)-4-(N'-benzyloxycarbonylamino)proline.

The crude product obtained in the preceding step is dissolved in 15 mlof ether and 15 ml of DCM at 0 ° C. 2.3 g of DIPEA and then 3.03 g ofbenzyl chloroformate in 5 ml of DCM are added, over 70 minutes at 0 ° C.After 3 hours, the solvents are evaporated at RT under vacuum; water andethyl acetate are added and the organic phase is washed successivelywith a potassium hydrogensulfate solution (3 times) , with water (3times) , with a sodium carbonate solution (3 times) , with water (3times) and with saline water. The product is chromatographed on silicaby eluting with hexane/AcOEt (40/60; v/v) mixture in order to obtain theexpected product.

α_(D) =-16.4 (c=0.3; chloroform).

F) Methyl ester of (2S, 4S)-(N-Boc)-4-(N'-benzyloxycarbonyl-N'-methyl)aminoproline.

2 g of the compound obtained in the preceding step are dissolved in 20ml of DMF at 0° C., under argon, in the presence of 2.25 g of methyliodide. 170 mg of 80% sodium hydride are added in portions and then themixture is stirred at 0° C. for 90 minutes. The mixture is extractedwith water and ethyl acetate; the organic phase is washed with water andthen saline water. The product is chromatographed on silica by elutingwith a hexane/AcOEt (50/50; v/v) mixture. 1.55 g of the expected productis obtained.

α_(D) =-38.8 (c=0.38; chloroform).

G)2',5-Dichloro-2-[(2S,4S)-N-(3,4-dimethoxyphenylsulfonyl)-N-(4-(N'-benzyloxycarbonyl-N'-methyl)amino-2-(methoxycarbonyl)pyrrolidinocarbonylmethyl)]-aminobenzophenone.

This product is obtained by the usual methods.

α_(D) =-22.4 (c=0.37; chloroform).

H)2-[(2S,4S)-4-(N-Benzyloxycarbonyl-N-methyl)amino-2-(methoxycarbonyl)pyrrolidinocarbonyl]-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline,cis isomer.

This product is obtained by cyclizing in the presence of DBU accordingto the usual methods. The crystals formed are crystallized fromDCM/isopropyl ether.

15 M.p.=129° C.

α_(D) =-129 (c=0.321; chloroform).

The isomeric purity by HPLC is 99%.

The compounds prepared in Examples 109a and 110a are used to prepare thecompounds according to the invention described in Table 5A below:

                  TABLE 5A                                                        ______________________________________                                         ##STR103##                                                                   Example R.sub.9             α.sub.D (chloroform)                        ______________________________________                                        111a cis                                                                              NH.sub.2            -189.6                                                                        c = 0.4                                           112a cis                                                                               ##STR104##         -174 c = 0.24                                     113a cis                                                                              NHCH.sub.3          -152.6                                                                        c = 0.28                                          114a cis                                                                              N(CH.sub.3).sub.2   -191                                                                          c = 0.19                                          ______________________________________                                    

The compound of Example 112a makes it possible to successively preparethe compounds of Examples 115a and 116a described in Table 6A below andthe compound of Example 114a makes it possible to prepare the compoundof Example 116b.

                  TABLE 6A                                                        ______________________________________                                         ##STR105##                                                                   Example R.sub.9             α.sub.D (chloroform)                        ______________________________________                                        115a cis                                                                               ##STR106##         -151 c = 0.27                                     116a cis                                                                              NH.sub.2            -161.4                                                                        c = 0.26                                          116b cis                                                                              N(CH.sub.3).sub.2                                                     ______________________________________                                    

The compound of Example 116b can be prepared either by conversion of thecompound of Example 114a, or from(2S,4S)-(N-Boc)-4-(dimethylamino)prolinamide, the preparation of whichis carried out as follows:

1) Methyl (2S,4S)-(N-Boc)-4-aminoprolinate is prepared from methyl(2S,4S)-4-azidoprolinate according to T. R. Webl in J. Org. Chem., 1991,56, 3009.

2) Methyl (2S,4S)-(N-Boc)-4-(dimethylamino)-prolinate.

4 g of the compound prepared in 1) are dissolved in 50 ml ofacetonitrile, 12.8 ml of 30% formalin are added and then, over 5minutes, 3 g of sodium cyanoborohydride. After the reactants have beenin contact for 2 hours, acetic acid is added to bring the solution to apH of 6. After 3 hours, the acetonitrile is evaporated, water, potassiumcarbonate and solid sodium chloride are added and the mixture isextracted with 4 volumes of ethyl acetate. The organic phase isevaporated, the residue is dissolved in 1N hydrochloric acid andextraction is carried out with AcOEt. Solid sodium carbonate and thensolid sodium chloride are added to the aqueous phase and extraction iscarried out with AcOEt. After evaporating, the residue is on silica gelby eluting with a DCM/MeOH (95/5; v/v) mixture and an oil whichsolidifies is isolated.

m=2.1 g

IR (DCM): 1755 cm⁻¹, 1695 cm⁻¹.

3) 534 mg of the ester prepared in 2) are dissolved in 4 ml of MeOH andare treated with sodium hydroxide (116 mg) in 1 ml of water for 48 hoursat RT. The mixture is acidified with 0.5N hydrochloric acid to a pH of3.5 and is evaporated to dryness. An azeotropic drying of the residue iscarried out in the presence of benzene (5 times) and then the residue isdried under vacuum for 8 hours. 2 ml of DMF and 3 ml of DCM are thenadded and the mixture is cooled to 0° C. 865 mg of BOP, and DIPEA, areadded to bring the reaction mixture to neutrality. After 15 minutes, astream of gaseous ammonia is bubbled through 2 times for 30 minutes.After 2 hours at RT, the DCM is evaporated, carbonated water and sodiumchloride are added and the mixture is extracted with 4 volumes of AcOEt.After evaporating, the residue is chromatographed on silica. The mixture(DCM/MeOH/NH4OH; 84.5/15/0.5; v/v/v) elutes a solid (m=185mg) which isrecrystallized from a DCM/isopropyl ether mixture.

M.p.=183°-186° C.

α_(D) =-63.1 (c=0.24; chloroform).

EXAMPLE 117a

Decarboxylation ofN-(2-carboxyethyl)-N-ethyl-3-(2-chlorophenyl)-5-chloro-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide,cis isomerism.

630 mg of the compound prepared in Example 41a are placed in solution in20 ml of THF under an argon atmosphere and then 101 mg ofN-methylmorpholine at -15° C. and 118 mg of isobutyl chloroformate areadded. After stirring for 5 minutes, 127 mg ofN-hydroxy-2-pyridinethione and 101 mg of TFA are added, the mixture isheld at -15° C. with stirring for 15 minutes, 900 mg oftert-butylmercaptan are then added and the mixture is left to return toRT. The reaction mixture is then irradiated for 1 hour 30 with atungsten filament lamp (150 watts). The mixture is concentrated, takenup in water, extracted with DCM and the extract dried and concentrated.The residue is chromatographed on silica by eluting with DCM/AcOEt(95/5; v/v). The expected product is obtained.

m=300 mg

M.p.=215° C.

This compound is similar to that of Example 125 described in theEuropean Patent Application EP 469984. It has the cis configurationaround the 2,3 bond of the indoline as in the starting material.

EXAMPLE 118a

Decarboxylation of2-((2R)-2-(carboxymethyl)pyrrolidinocarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline,cis isomer.

The operation is carried out as in the preceding example from thecompound described in Example 102a.

The product obtained is recrystallized from a

DCM/isopropyl ether mixture.

M.p.=215°-220° C.

α_(D) =-214.5° (c=0.2; chloroform).

This compound is2-((2S)-2-methylpyrrolidino-carbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline,cis isomerism.

EXAMPLE 119a

Decarboxylation of2-(2-carboxypyrrolidinocarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline,cis isomer.

The operation is carried out as in the preceding example by using thecompound prepared in Example 28a as the starting material. The productobtained is recrystallized from an isopropyl ether/DCM mixture.

M.p.=263° C.

α_(D) =-201.5° (c=0.2; chloroform).

This compound is2-pyrrolidinocarbonyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3hydroxyindoline,cis isomer.

What is claimed is:
 1. A compound of formula: ##STR107## in which: R'₁is a halogen atom, a C₁ -C₄ alkyl, a hydroxyl, a C₁ -C₄ alkoxy, abenzyloxy group, a cyano group, a trifluoromethyl group, nitro group oran amino group;R'₂ is a C₁ -C₆ alkyl, a C₃ -C₇ cycloalkyl, C₅ -C₇cycloalkene or a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a C₁ -C₄ alkyl, a C₁ -C₄ alkoxy, a halogen, atrifluoromethyl group or an amino group, or R'₂ is a nitrophenyl whichis unsubstituted or monosubstituted by a trifluoromethyl group ormonosubstituted or polysubstituted by a C₁ -C₄ alkyl or a halogen; R'₃is a hydrogen atom; R'₄ is a carbamoyl group of formula CONR'₆ R'₇ ; R'₅is a C₁ -C₄ alkyl; a 1-naphthyl; a 2-naphthyl; a5-dimethylamino-1-naphthyl; a phenyl which is unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of a halogen atom, a C₁ -C₄ alkyl, a trifluoromethyl group,an amino group which is free or substituted by one or two C₁ -C₄ alkyls,a hydroxyl, a C₁ -C₄ alkoxy, a C₂ -C₄ alkenoxy, a C₁ -C₄ alkylthio, atrifluoromethoxy group, a benzyloxy group, a cyano group, a carboxylgroup, a C₁ -C₄ alkoxycarbonyl group, a carbamoyl group which is free orsubstituted by one or two C₁ -C₄ alkyls or a C₁ -C₄ alkylamino group, orR'₅ is a nitrophenyl which is unsubstituted or monosubstituted by atrifluoromethyl group or a C₂ -C₄ alkenoxy or mono- or polysubstitutedby a halogen, a C₁ -C₄ alkyl, a C₁ -C₄ alkoxy, a C₁ -C₄ alkylthio, atrifluoromethoxy group or a benzyloxy group; R'₆ and R'₇ together, withthe nitrogen atom to which they are connected, form a saturated,5-membered ring containing a single nitrogen atom and substituted by R₈and R₉ ; R₈ is R'₈ is a group (CH₂)_(q) which is itself substituted by acarboxyl group, a C₁ -C₄ alkoxycarbonyl group, a benzyloxycarbonylgroup, a carbamoyl group which is free or substituted by a hydroxyl orby one or two C₁ -C₄ alkyls or an aminocarbothioyl group which is freeor substituted by one or two C₁ -C₄ alkyls; R₉ is hydrogen, a halogen, agroup (CH₂)_(r) OR₁₀, a group (CH₂)_(r) NR₁₁ R₁₂, a group (CH₂)_(t)CONR₁₁ R'₁₁ or an azido group; R₁₀ is hydrogen, a C₁ -C₄ alkyl, a mesylor a tosyl; R₁₁ and R'₁₁ and R₁₂ are each a hydrogen or a C₁ -C₄ alkylor R₁₁ is hydrogen and R₁₂ is a benzyloxycarbonyl or a C₁ -C₄alkoxycarbonyl; n is 0, 1 or 2; m is 0, 1 or 2; q is 0, 1, 2 or 3; r is0, 1, 2 or 3, with the limitation that r is not zero when R₈ and R₉ isat the alpha-position of the intracyclic amide nitrogen; t is 0 or 1;aswell as its possible salts.
 2. A compound of formula (I"): ##STR108## inwhich: R"₁ is a halogen atom, a C₁ -C₄ alkyl, a hydroxyl, a C₁ -C₄alkoxy, a benzyloxy group, a cyano group, a trifluoromethyl group, nitrogroup or an amino group;R"₂ is a C₁ -C₆ alkyl, a C₃ -C₇ cycloalkyl, a C₅-C₇ cycloalkene or a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a C₁ -C₄ alkyl, a C₁ -C₄ alkoxy, a halogen, atrifluoromethyl group or an amino group, or R"₂ is a nitrophenyl whichis unsubstituted or monosubstituted by a trifluoromethyl group ofmonosubstituted or polysubstituted by a C₁ -C₄ alkyl or a halogen; R"₃is a hydrogen atom; R"₄ is a carbamoyl group of formula CONR"₆ R"₇ ; R"₅is a C₁ -C₄ alkyl; a 1-naphthyl; a 2-naphthyl; a5-dimethylamino-1-naphthyl; a phenyl which is unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of a halogen atom, a C₁ -C₄ alkyl, a trifluoromethyl group,an amino group which is free or substituted by one or two C₁ -C₄ alkyls,a hydroxyl, a C₁ -C₄ alkoxy, a C₂ -C₄ alkenoxy, a C₁ -C₄ alkylthio, atrifluoromethoxy group, a benzyloxy group, a cyano group, a carboxylgroup, a C₁ -C₄ alkoxycarbonyl group, a carbamoyl group which is free orsubstituted by one or two C₁ -C₄ alkyls or a C₁ -C₄ alkylamino group, orR"₅ is a nitrophenyl which is unsubstituted or monosubstituted by atrifluoromethyl group or a C₂ -C₄ alkenoxy or mono- or polysubstitutedby a halogen, a C₁ -C₄ alkyl, a C₁ -C₄ alkoxy, a C₁ -C₄ alkylthio, atrifluoromethoxy group or a benzyloxy group; R"₆ and R"₇, together withthe nitrogen atom to which they are connected, form a saturated5-membered ring containing a single nitrogen atom and substituted by ahydroxyl in a position which is other than the alpha-position of thenitrogen of the ring, a group (CH₂)_(r) OH, or a group (CH₂)_(r) itselfsubstituted by an amino group which is free or substituted by one or twoC₁ -C₄ alkyls, or a group (CH₂)_(q) itself substituted by a carboxylgroup, a C₁ -C₄ alkoxycarbonyl, a benzylcarbonyl group, a carbamoylgroup which is free or substituted by a hydroxyl or one or two C₁ -C₄alkyls; n is 0, 1 or 2; m is 0, 1 or 2; q is 0, 1, 2 or 3; r is 0, 1, 2or 3;as well as its possible salts.
 3. A compound as claimed is claim 1in which R'₁ is a chlorine or bromine atom or a methoxy group and n=1.4. A compound as claimed is claim 1 in which R'₂ is a chlorophenyl or amethoxyphenyl or a cyclohexyl.
 5. A compound as claimed is claim 1 inwhich R'₅ is a phenyl substituted at the 3- and 4-positions or at the 2-and 4-positions by a methoxy group, or else R'₅ is a phenyl substitutedat the 4-position by a methyl.
 6. A compound as claimed is claim 1 inwhich m=0.
 7. A compound as claimed is claim 1 in which R'₄ is CONR'₆R'₇ and NR'₆ R'₇ is a pyrrolidino group substituted at the 2-position bya group (CH₂)_(q) which is itself substituted by a carboxyl group, or acarbamoyl group with q=0, 1, 2 or
 3. 8. A compound as claimed is claim 1in which R'₄ is CONR'₆ R'₇ and NR'₆ R'₇ is a pyrrolidino groupsubstituted at the 2-position by a group (CH₂)_(q) which is itselfsubstituted by a carboxyl group or a carbamoyl group.
 9. A compound asclaimed is claim 1 in the from of a cis isomer in which R'₂ and R'₄ areon the same side of the indoline ring.
 10. A pharmaceutical compositioncomprising a compound as claimed in claim 1 as the active principle. 11.A compound of formula (I') as claimed in claim 1 in whichR'₂ is a phenylwhich is substituted by a halogen; R'₃ is hydrogen; R'₄ is CONR'₆ R'₇and CONR'₆ R'₇ is a pyrrolidino group substituted at the 2-position byR₈, where R₈ is a carbamoyl group; R'₅ is a dimethoxyphenyl group; and mis
 0. 12. A compound according to claim 11 which is2-((2S)-2-carbamoylpyrrolidino-carbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-indoline.